IE68842B1 - New cyclic amine derivatives pharmaceutical compositions containing these compounds and processes for their preparation - Google Patents

New cyclic amine derivatives pharmaceutical compositions containing these compounds and processes for their preparation

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Publication number
IE68842B1
IE68842B1 IE155988A IE155988A IE68842B1 IE 68842 B1 IE68842 B1 IE 68842B1 IE 155988 A IE155988 A IE 155988A IE 155988 A IE155988 A IE 155988A IE 68842 B1 IE68842 B1 IE 68842B1
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Ireland
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methyl
oxo
dimethoxy
group
ethyl
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IE155988A
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IE881559L (en
Inventor
Joachim Dr Heider
Manfred Dr Psiorz
Andreas Dr Bomhard
Norbert Dr Hauel
Berthold Dr Narr
Klaus Dr Noll
Jurgen Dr Dammgen
Christian Dr Little
Walter Prof Dr Kobinger
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Thomae Gmbh Dr K
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Publication of IE881559L publication Critical patent/IE881559L/en
Publication of IE68842B1 publication Critical patent/IE68842B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Abstract

Cyclic amine derivatives of the formula <IMAGE> in which A, B, E, G, R, R1, R2, m and n are as defined in Claim 1, their enantiomers, their diastereomers, their N-oxides and their acid addition salts have useful pharmacological properties, in particular a bradycardic action. The novel compounds can be prepared by processes known per se.

Description

New cyclic amine derivatives, pharmaceutical compositions containing these compounds and processes for their preparation British Patent 1 548 844 describes 3,4-dihydro-2isoquinolin-l-ones and 1,2,3,4-tetrahydro-5H-25 benzazepin-l-ones and EP-A-0,065,229 describes 2H-3benzazepines. Thus, Example 82 of EP-A-0,065,229 describes the one compound in which E denotes a branched alkylene group, namely 1- [7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-on-3-yl]-2-methyl-3-[N10 methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino]propane. The abovementioned compounds and the physiologically acceptable acid addition salts thereof have valuable pharmacological properties, namely, not only a mild hypotensive activity but more particularly a selective heart rate lowering activity.
Surprisingly, it has now been found that the new cyclic amine derivatives of general formula the enantiomers, diastereomers, N-oxides and acid addition salts thereof, particularly their physiologically acceptable acid addition salts with inorganic or organic acids, have even more valuable pharmacological properties, particularly a hypotensive effect and a long-lasting heart rate lowering activity and the effect of reducing the O2 requirement of the heart.
The present invention thus relates to the new cyclic amine derivatives of general formula (I) above, the enantiomers, diastereomers, N-oxides and acid addition - 2 salts thereof, and more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof with inorganic or organic acids, processes for their preparation and pharmaceutical compositions containing these compounds.
In general formula (I) above: A represents a -CH2-, -CH2-CH2- or -CH=CH- group, x B represents a -CH2-, -CH2-CH2-, -CO- or -CH2CO group, whilst the carbon atom marked x is linked to the phenyl nucleus, E represents a straight-chained Ci_3-alkylene group, G represents a straight-chained Ci-e-alkylene group, wherein a methylene group, linked to an aromatic or heteroaromatic group R, of a straight-chained C3.6alkylene group may be replaced by an oxygen atom, or by a methyl imino or ethyl imino group, m represents the number 1, 2, 3, 4, 5 or 6 and n represents the number 0, 1, 2 or 3, although n + m must represent the number 3, 4, 5 or 6, R1 represents a methyl or methoxy group, Λ R2 represents a methyl or methoxy group or R^ and R2 together represent a methylenedioxy group and j λ R represents an optionally methyl-substituted furyl, thienyl, pyridyl, benzo[b]furyl or benzo[b]thienyl group, a benzo [b] thienyl group substituted by a halogen atom or by a methoxy or methanesulphonyloxy group, an indolyl or N-methyl-indolyl group optionally substituted by a hydroxy, methoxy or benzyloxy group, a dimethyl-thienyl or dime thoxy-isoquinolyl group, a naphthyl group optionally mono- or disubstituted by methyl or methoxy groups, whilst the substituents may be identical or different, or, if B represents a -CH2- or -CO- group, a phenyl group optionally substituted by a methylenedioxy group, a phenyl group mono- or disubstituted by a chlorine or bromine atom or methyl or methoxy groups, whilst the substituents may be identical or different, a phenyl group substituted by a hydroxy, benzyloxy, methanesulphonyloxy, trifluoromethane sulphonyl oxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetamido, methanesulphonylamino or bis (methanesulphonyllamino group, or a trimethoxyphenyl, tetramethylphenyl or dihaloaminophenyl group.
The following compounds which fall within the scope of protection of this invention but are not explicitly described in the Examples will now be mentioned by way of example: 2- [ (N- (2- (naphth-2-yl) -ethyl) - hexahydro-az epin3- yl) -methyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline , 2- [ (N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)methyl] -6,7 -dimethoxy-1,2,3,4-tetrahydro-isoquinoline, - [ (N- (2- (naphth-l-yl) -ethyl) -hexahydro-azepin3- yl) -methyl] -6,7-dimethoxy-1 -oxo-1,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2- (naphth-l-yl) -ethyl) -azacyclooct-3-yl) methyl] -6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline , 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -pyrrolid-3yl) -methyl] -6,7-dimethoxy-1-oxo-l, 2,3,4-tetrahydroisoquinoline , 2- [3- (N- (2-methyl-naphth-l-yl) -methyl) -piperid3- yl)-propyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl) pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline , 2-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)-ethyl) azacyclooct-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4k tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -hexahydroazepin-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-azacyclooct3- yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2- [3- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -pyrid3- yl)-propyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline , 2-[(N-(4-(naphthyl-2-oxy)-butyl)-azacyclooct-3yl)-methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline, 2- [2- (N- (4- (naphthyl-2-oxy) -butyl) -piperid-2-yl) ethyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro- j isoquinoline, * 2-[(N-(3-(naphthyl-2-oxy)-propyl)-azacyclooct-3yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydroisoquinoline, 2- [ (N- (3- (naphth-2-yl) -propyl) -piperid-3-yl) -methyl] 6,7-dimethoxy-l,2,3,4-tetrahydro-isoquinoline, 2- [ (Ν- (3- (naphth-2-yl) -propyl) -azacyclooct-3-yl) methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] 6, 7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline, 2- [ (N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro1q isoquinoline, 2- [ (N- (2-methyl-naphth-1-yl) -methyl) -pyrrolid-3yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro isoquinoline, 2- ((N- (2-methyl-naphth-1-yl) -methyl) -piperid-3yl)-methyl]-6,7 -methylenedioxy-1,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2-methyl-naphth-1-yl) -methyl) -azacyclooct3- yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) 25 azacycl6oct-3-yl) -methyl] -6,7-methylenedioxy-1oxo-1,2,3,4-tetrahydro-isoquinoline, 2- [2- (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) piperid-3-yl) -methyl] -6,7-methylenedioxy-1-oxo30 1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid3- yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4tetrahydro-isoquinoline, 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -pyrrolid-3-yl) methyl] -6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydroisoquinoline, 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -piperid-3-yl) methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydroisoquinoline , 2- [(N-(4-(naphthyl-2-oxy)-butyl)-hexahydro-azepin 3- yl)-methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline , 2-[(N-(2-(naphth-2-yl)-ethyl)-pyrrolid-3-yl)-methyl] 6.7- dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] 6.7- dimethyl-1,2,3,4-tetrahydro-isoquinoline, 2-[(N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2-[(N-(2-(naphth-2-yl)-ethyl)-azacyclooct-3-yl)methyl]-6,7-dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (naphth-l-yl) -ethyl) -pyrrolid-3-yl) -methyl] 6.7- dimethyl-l,2,3,4-tetrahydro-isoquinoline, 2- [(N-(2-(naphth-l-yl)-ethyl)-hexahydro-azepin3- yl)-methyl)-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline , 2- [3- (N- (2- (naphth-l-yl) -ethyl) ;-piperid-3-yl) -propyl] 6.7- dimethyl-l-oxo-l, 2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -piperid-3yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline , 2-[(N-(2-methyl-naphth-l-yl)-methyl)-piperid-3yl)-methyl]-6,7-dimethyl-1,2,3,4-tetrahydro- » isoquinoline, 2- [ (N- (2-methyl-naphth-l-yl) -methyl) -azacyclooct3- yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline , 2- [2- (N- (2-methyl-naphth-l-yl)-methyl)-piperid2-yl)-ethyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2- I (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) 10 piperid-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) hexahydro-azepin-3-yl) -methyl] -6,7-dimethyl-1-oxo15 1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) azacyclooct-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) azacyclooct-3-yl) -methyl] -6,7-dimethyl-1,2,3,4tetrahydro-isoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -pyrrol id3- yl) -methyl] -6,7-dimethyl-l,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid30 3-yl) -methyl] -6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -hexahydroazepin-3-yl) -methyl] -1,2,3,4-tetrahydro-isoquinoline, 2- [2- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid2-yl)-ethyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2- I (N- (4- (naphthyl-2-oxy) -butyl) -piperid-3-yl) methyl] -6,7-dimethyl -1 -oxo-1,2,3,4-tetrahydroisoquinoline , 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -hexahydro-azepin3- yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, 2- [ (N- (4- (naphthyl-2-oxy) -butyl) -azacyclooct-3-yl) methyl] -6,7-dimethyl-1,2,3,4-tetrahydro-isoquinoline, 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) -propyl) -hexahydroazepin-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4tetrahydro- isoquinoline, 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) -propyl) -azacyclooct3- yl) -methyl] -6,7-dimethyl-1-oxo-l,2,3,4-tetrahydroisoquinoline, 2- [ (N- (3- (5,6-dimethoxy-naphthyl-2-oxy) -propyl) azacyclooct-3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [ (N- (3- (naphthyl) -propyl) -azacyclooct-3-yl) -methyl] 6.7 -dimethyl -1 - oxo -1,2,3,4- tetrahydro- isoquinol ine, 3- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] 7,8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro-2H3-benzazepine; 3- [ (N- (l- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] 7.8 -methylenedioxy-1,3,4,5 - tetrahydro- 2H- 3 -benzazepine, 3- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] 7,8 - dimethyl -1,3,4,5- tetrahydro- 2H- 3 -benzazepine, 2- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] 6,7-dimethyl-1-oxo-l, 2,3,4-tetrahydro-isoquinoline, 2- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] 5.6- methylenedioxy-1-oxo-1,3-dihydro-isoindole, 2- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] 5,6 -methylenedioxy-1,3 -dihydro- isoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid3- yl) -methyl] -5,6-methylenedioxy-l-oxo-l, 3-dihydroisoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrol id3- yl) -methyl] -5,6-methylenedioxy-1,3-dihydro-isoindole, 2- [ (N- (l- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] 5,6 - dimethyl -1,3 -dihydro- isoindole, 3- [ (N- (3- (pyrid-3-yl) -propyl) -pyrrolid-3-yl) -methyl] 7,8 -dimethoxy-1,3,4,5- tetrahydro- 2H-3 -benzazepine, 2- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid-3-yl) -methyl] 5,6 -dimethoxy-1,3 -dihydro- isoindole, 2-[(N-(1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] 5.6- dimethoxy-1,3-dihydro-isoindole, 2- t (N- (1- (pyrid-3-yl) -methyl) -pyrrolid-3-yl) -methyl] 5.6- dimethoxy-1-oxo-1,3-dihydro-isoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl, -ethyl, -pyrrolid3- yl) -methyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -pyrrolid3- yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 2- [ (N- (2- (6-methy 1-pyrid-2-yl) -ethyl) -pyrrolid3- yl) -methyl] -6,7-dimethoxy-1 -oxo-1,2,3,4-tetrahydroisoquinoline, 2- [ (N- (2-(6-methyl-pyrid-2 -yl) -ethyl) -pyrrolid3- yl) -methyl] -5,6-dimethoxy-l-oxo-1,3-dihydro-isoindole, 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] 6.7- dimethoxy-1,2,3,4-tetrahydro-isoquinoline, 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] 6.7- dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline, 3- [ (N- (2- (6,7-dimethoxy-isoquinol-4-yl) -ethyl) piperid-2-yl) -methyl] -7,8-dimethyl-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine, 2- [ (N- (1- (pyrid-4-yl) -methyl) -piperid-3-yl) -methyl] 6,7 -dimethyl -1,2,3,4- tetrahydro- isoquinoline t 2- [ (N- (2- (6, 7-dimethoxy-isoquinol-4-yl) -ethyl) piperid-3-yl)-methyl] -5,6-methylenedioxy-1-oxo1,3-dihydro-isoindole, 2- [2- (N- (3- (pyrid-4-yl) -propyl) -piperid-2-yl) -ethyl] 5,6-methylenedioxy-1,3-dihydro-isoindole, 2- [ (N- (3- (pyrid-3-yl) -propyl) -hexahydro-azepin3- yl) -methyl] -6,7-dimethyl-l-oxo-1,2,3,4-tetrahydroisoquinoline, - [ (N- (3- (pyrid-3-yl) -propyl) -hexahydro-azepin3-yl) -methyl] -6,7-dimethyl-l, 2,3,4-tetrahydroisoquinoline , 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) - hexahydroazepin-3-yl) -methyl] -5,6-dimethoxy-1,3-dihydroisoindole, 2- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) -hexahydroazepin-3-yl) -methyl] -5,6-dimethoxy-1-oxo-l, 3-dihydroisoindole. - 11 3- [ (Ν- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 2- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid3-yl)-methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline , 3- [ (N- (3- (5-methoxy-indol-3-yl) -propyl) -pyrrolid10 3-yl)-methyl]-7,8-dimethyl-1,3,4,5-tetrahydro-2H3-benzazepine, - [ (N- (3 - (5 -methoxy- indol -3 -yl) -propyl) -pyrrolid3-yl) -methyl] -5,6-methylenedioxy-1,3-dihydro-isoindole, 2- ((N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid3- yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline, 2-[ (N-(3-(5-benzyloxy-indol-3-yl)-propyl)-pyrrolid3-yl)-methyl]-5,6-methylenedioxy-l-oxo-l,3-dihydroisoindole, 3-[ (N-(3-(N-methyl-indol-3-yl)-propyl)-pyrrolid25 3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro2H-3-benzazepine, 2- [ (N- (3- (N-methyl-indol-3-yl) -propyl) -pyrrolid3- yl) -methyl]-6,7-dimethyl-1,2,3,4-tetrahydro30 isoquinoline, 2- [ (N- (3- (indol-3-yl) -propyl) -pyrrolid-3-yl) -methyl] 5,6-dimethyl-1,3-dihydro-isoindole, 3- [ (N- (3- (indol-3-yl) -propyl) -pyrrolid-3-yl) -methyl] 7,8-dimethoxy-2-oxo-1,3,4,5 - tetrahydro-2H-3-benzazepine, 2- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid35 - 12 3-yl)-methyl]-5,6-dimethyl-1-oxo-l,3-dihydro-isoindole, 2- [ (N- (3- (5-hydroxy-indol-3-yl) -propyl) -pyrrolid3- yl)-methyl]-6,7-dimethoxy-1-oxo-l, 2,3,4-tetrahydro5 isoquinoline, 3- [ (N- (3- (5-methoxy-indol-3-yl) -propyl) -pyrrolid3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepine, 2- [ (N- (3- (5-methoxy-indol-3-yl) -propyl, -pyrrolid3- yl)-methyl]-5,6-dimethoxy-1-oxo-l,3-dihydro-isoindole, 2- [ (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid15 3-yl) -methyl] -6,7-dimethoxy-l,2,3,4-tetrahydroisoindole, 2- [ (N- (3- (5-benzyloxy-indol-3-yl) -propyl) -pyrrolid3- yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro20 isoquinoline, 2- [ (N- (3- (N-methyl-indol-3-yl) -propyl) -pyrrolid3- yl) -methyl] -5,6-dimethyl-1-oxo-l, 3-dihydro-isoindole, 2- [ (N- (3- (N-methyl-indol-3-yl) -propyl) -pyrrolid3-yl) -methyl] -5,6-dimethoxy-1,3-dihydro-isoindole, 2- [ (N- (2- (3,4-dimethoxy-phenyl) -ethyl) -hexahydroazepin-3-yl)-methyl]-6,7-methylenedio3Qr-l-oxo-l,2,3,430 tetrahydro-isoquinoline, 2- [ (N-(3- (3,4-methylenedioxy-phenoxy) -propyl) -hexahydroazepin-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline, 2- [ (N- (2- (4-trifluoromethoxy-phenyl) -ethyl) -piperid3- yl) -methyl] -5,6-dimethoxy-1-oxo-l, 3-dihydro-isoindole, 2- [(N-(2-(4-trifluoromethyl-phenyl)-ethyl)-piperid3- yl) -methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[ (N-(2-(3,4-dichloro-phenyl)-ethyl)-piperid-35 yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole,. 2- [(N-(2-(3,4,5-trimethoxy-phenyl)-ethyl)-piperid3- yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(4-methoxy-phenyl)-ethyl)-piperid-3-yl)methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(3-methyl-phenyl)-ethyl)-piperid-3-yl)methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2- [ (N- (2-(3,4-dimethyl-phenyl) -ethyl) -piperid-3yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(2,3,4,5-tetramethyl-phenyl)-ethyl)-piperid20 3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[ (N-(2-(4-benzyloxy-phenyl)-ethyl)-piperid-3yl) -methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[ (N-(2-(4-hydroxy-phenyl)-ethyl)-piperid-3-yl)methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(2-(4-methanesulphonyloxy-phenyl)-ethyl)piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro3Q isoindole, 2-[(N-(2-(4-trifluoromethanesulphonyloxy-phenyl)ethyl) -piperid-3-yl) -methyl] -5,6-dimethoxy-1-oxo1,3-dihydro-isoindole, 2-[(N-(2-(4-methanesulphonylamino-phenyl)-ethyl)piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydroisoindole, 2- [ (Ν- (2-(4-dimethanesulphonylamino-phenyl)-ethyl)piperid-3-yl)-methyl] -5,6-dimethoxy-l-oxo-l,3-dihydroisoindole, 2-[(N-(3-(4-bromo-phenyl)-propyl)-piperid-3-yl)methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, - [ (N-(3-(4-methoxy-phenyl)-propyl)-piperid-3-yl)methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N- (3-(3-methoxy-phenyl)-propyl)-piperid-3-yl) methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole, 2- [(N-(3-(3,4-dimethoxy-phenyl)-propyl)-piperid3- yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydro-isoindole, 2-[(N-(4-(4-methoxy-phenyl)-butyl)-piperid-3-yl)methyl] -5., 6-dimethoxy-l-oxo-l, 3-dihydro-isoindole, 2- [ (N- (3- (4-amino-3,5-dibromo-phenoxy) -propyl) piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydroisoindole, 3- [(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N--(2- (5-methoxy-benzo [b] thienyl-3) -ethyl) -piperid3-yl)-methyl]-7,8-diraethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (2- (6-methoxy-benzo [b] thienyl-3) -ethyl) -piperid3-yl)-methyl]-7,8-diraethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(6-bromo-benzo[b]thienyl-3)-ethyl)-piperid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (2- (benzo [b] thienyl-2, -ethyl) -piperid-3-yl) methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-3)-ethyl)-piperid-3-yl)methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid10 3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(5-methoxy-benzo[b]thienyl-3)-ethyl)-piperidy 3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro15 2H-3-benzazepine, 3-[(N-(2-(6-methoxy-benzo[b]thienyl-3)-ethyl)-piperid3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(6-bromo-benzo[b]thienyl-3)-ethyl)-piperid3-yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo[b]thienyl-2)-ethyl)-piperid-3-yl)methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(2-(benzo[b]furyl-3,-ethyl,-piperid-3-yl,30 methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(2-(2,5-dimethyl-thien-3-yl)-ethyl)-piperid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,53g tetrahydro-2H-3-benzazepine, 3-[(N-(2-(5-methoxy-benzo[b]thienyl-3)-ethyl)-piperid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,516 tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (6-methoxy-benzo[b] thienyl-3) -ethyl) -piperid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (6-bromo-benzo[b] thienyl-3) ethyl) -piperid3 -yl) -methyl ] - 7,8 -methylenedioxy- 2 - oxo-1,3,4,5tetrahydro-2H-3-benzazepine, 3-[ (N-(2-(benzo[b]thienyl-2)-ethyl)-piperid-3-yl)methyl[-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (2- (benzo[b] furyl-3) -ethyl) -piperid-3-yl) methyl]-7,8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (3- (2,5 - dime thyl-thien-3-yl) -propyl) -piperid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (3- (5-methoxy-benzo[b] thienyl-3) -propyl) piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine, 3- [ (N- (3- (6-methoxy-benzoCb] thienyl-3) -propyl) piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine, 3-[(N-(3-(6-bromo-benzo[b]thienyl-3)-propyl)-piperid3-yl) methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(3-(benzo[b]thienyl-2)-propyl)-piperid-3- yl) methyl] -7, 8 - dime thoxy- 2 - oxo -1,3,4,5-tet rahydro 2H-3-benzazepine, 3- [ (N- (3- (benzo [bl furyl-3) -propyl) -piperid-3-yl) methyl1-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(3-(2,5-dimethyl-thien-3-yl)-propyl)-piperid3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (3- (6-methoxy-benzo [b] thienyl-3) -propyl) piperid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine, 3-[(N-(3-(benzo[b]thienyl-2)-propyl)-piperid-3yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(3-(benzo[b]furyl-3)-propyl)-piperid-3-yl)methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(3-(2,5-dimethyl-thien-3-yl)-propyl)-piperid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine, 3-[(N-(3-(6-methoxy-benzo[b]thienyl-3)-propyl)piperid-3-yl) -methyl] -7,8-methylenedioxy-2-oxo1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(3-(benzo[b]thienyl-2)-propyl)-piperid-3yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (3- (benzo[b] furyl-3) -propyl) -piperid-3-yl) methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (2- (thien-2-yl) -ethyl) -piperid-3-yl) -methyl] 7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3- [ (N- (2- (benzo [b] thienyl-3) -ethyl) -piperid-3-yl) methyl] -7, 8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3 -benzazepine ,· 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) methyl] -7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3- [ (N- (2- (thien-2-yl) -ethyl) -piperid-3-yl) -methyl] 7,8-methylenedioxy-2-oxo.-l, 3,4,5-tetrahydro-2H3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -piperid-3-yl) methyl] -7, 8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro2Ή-3-benzazepine, 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) methyl] -7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- ((N- (2- (thien-2-yl) -ethyl) - hexahydro-azepin-3- yl) methyl] -7, 8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (2- (benzo [b] thienyl-3) -ethyl) -hexahydro-azepin3-yl) -methyl] -7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3- (N- (2- (benzo[b] furyl-2) -ethyl) -hexahydro-azepin3-yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H- 3-benzazepine, 3-1 (N- (2- (thxen-2-yl) -ethyl) -hexahydro-azepin-3yl) -methyl] -7,8-methylenedioxy-2-oxo-l, 3,4,5-tetrahydro2H- 3-benzazepine, 3- [ (N- (2- (benzo[b] thienyl-3) -ethyl) -hexahydro-azepin-r 3-yl) -methyl] -7,8-methylenedioxy-2-oxo-l,3,4,519 tetrahydro-2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]7, 8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(2-(benzo[b]thienyl-3)-ethyl,-pyrrolid-3yl)-methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-pyrrolid-3-yl)methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]7.8- methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(2-(benzo[b]thienyl-3)-ethyl)-pyrrolid-3yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro 2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-pyrrolid-3-yl)methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(thien-2-yl)-ethyl)-pyrrolid-3-yl)-methyl]7.8- dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine 3-[(N-(2-(benzo[b]thienyl-3)-ethyl,-pyrrolid-3yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-pyrrolid-3-yl)methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro20 2H-3-benzazepine, 3-[(Ν-(2-(thien-2-yl)-ethyl)-hexahydro-azepin-3yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo(b]thienyl-3)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(2-(benzo[b]furyl-2)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(4-(thien-2-yl)-butyl)-piperid-3-yl)-methyl]7.8- dimethyl-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(4-(benzo[b]thienyl-3)-butyl)-piperid-3-yl)methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)methyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro-2H3-benzazepine, 3- [ (N- (5- (thien-2-yl) -pentyl) -piperid-3-yl) -methyl] 7.8- dimethyl-2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine, 3-[(N-(5-(benzo[b]thienyl-3)-pentyl)-piperid-3yl)-methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3- [ (N- (5- (benzo[b] furyl-2) -pentyl) -piperid-3-yl) methyl]-7,8-dimethyl-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(4-(thien-2-yl)-butyl)-piperid-3-yl)-methyl]7.8- methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H21 3-benzazepine, 3-[(N-(4-(benzo[b]thienyl-3)-butyl)-piperid-3-yl)methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(5-(thienyl-2)-pentyl)-piperid-3-yl)-methyl]7,8-methylenedioxy-2-oxo-l,3,4,5-tetrahydro-2H3-benzazepine, 3-[(N-(5-(benzo[b]thienyl-3)-pentyl)-piperid-3yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(5-(benzo[b]furyl-2)-pentyl)-piperid-3-yl)methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydrO2H-3-benzazepine, - [ (N- (4- (benzo[b] thienyl-3) -butyl) -piperid-3-yl) methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(4-(benzo[b]furyl-2)-butyl)-piperid-3-yl)methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 3-[(N-(5-(benzo[b]thienyl-3)-pentyl)-piperid-3yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine and 3- [ (N- (5- (benzo[b] furyl-2) -pentyl) -piperidyl-3) methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine and the enantiomers, diastereomers, N-oxides and acid addition salts thereof, more particularly, for pharmaceutical use, the physiologically acceptable acid addition salts thereof.
Preferred compounds of general formula (I) above, however, are those of general formula (Ia) ΊΟ / CH \ (Ia) (CH2)n wherein R, R ,' R2, R, A, Β, E, G, m and n are defined as hereinbefore , and the enantiomers, diastereomers, N-oxides and acid 20 addition salts thereof.
Particularly preferred confounds of general formula (I), however, are those wherein A represents a -CH2CH2- group, x B represents a -CH2-CH2_, -CO- or -CH2CO- group, wherein the carbon atom designated x is linked to the phenyl nucleus, E represents a methylene or ethylene group, G represents a straight-chained C2-4-alkylene group, wherein a methylene group of a straight-chained C3.435 alkylene group, linked to an aromatic or heteroaromatic group R, may be replaced by an oxygen, Rx represents a methoxy group,.
R2 represents a methoxy group or Rx and R2 together represent a methylenedioxy group, m represents the number 2, 3 or 4, n represents the number 1 and R represents a naphth-2-yl, 6-methoxy-naphth-2-yl, -methyl-6-methoxy-naphth-2-yl, thien-2-yl, 6-methylpyrid-2-yl, benzo[b]fur-2-yl or benzo[b]thien-3-yl group or, if B represents a -CO- group, a 4-methoxyphenyl or 3,4-dimethoxyphenyl group, the enantiomers, diastereomers and acid addition salts thereof.
The following are particularly preferred compounds: a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3benzazepine, b) 3- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine, c) 3- [2- (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -piperid2- yl) -ethyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, d) 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -hexahydroazepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo1,2,3,4-tetrahydro-isoquinoline, e) 2- [ (N- (2- (naphth-2-yl) -ethyl) -hexahydro-azepin3- yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline, f) 2- [ (N- (2-(3,4-dimethoxy-phenyl) -ethyl) -piperid3 -yl) -methyl 1-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline, g) 2- [ (N- (2-(3,4-dimethoxy-phenyl) -ethyl) -piperid3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, h) 2- [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid-3yl) -methyl] -6,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline, i) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] 7,8 -dimethoxy-2 -oxo-1,3,4,5 - tetrahydro-2H-3 benzazepine, / k) 3- [ (N- (2- (benzo [b] furyl-2) -ethyl) -piperid-3-yl) methyl] -7,8 -dimethoxy-2 -oxo-1,3,4,5-tetrahydro2H-3-benzazepine, l) 3- [ (N- (2- (benzo tb] thienyl-3) -ethyl) -piperid-3-yl) methyl] -7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, m, 2- [ (N- (3- (6-methoxy-naphthyl-oxy) -propyl) -pyrrol id3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4tetrahydro-isoquinoline and n) 2 - [ (N- (2-(6-methoxy-naphth-2 -yl) -ethyl) -hexahydroazepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo1,2,3,4-tetrahydro-isoquinoline, but particularly the following compounds: a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) -methyl] 7,8-dimethoxy-2-oxo-1,3,4,5 - tetrahydro-2H- 3 benzazepine. b) 2- [ (Ν- (3- (4-methoxy-phenoxy) -propyl) -piperid-3yl)-methyl]-6,7-dimethyl-1-oxo-l,2,3,4-tetrahydroisoquinoline, c) 3-[(N-(4-(thienyl-2)-butyl)-piperid-3-yl)-methyl]7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3benzazepine, d) 2-[(N-(3-(6-methoxy-naphthyl-2-oxy)-propyl)pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline, e) 2- [ (N- (2-(6-methoxy-naphth-2-yl)-ethyl)-hexahydroazepin-3-yl)-methyl]-6,7-methylenedioxy-l-oxo1.2.3.4- tetrahydro-isoquinoline, f) 3-[(N-(2-(4-methoxy-phenyl)-ethyl)-hexahydro-azepin3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine and g) 3- [ (N- (2- (3,4-dimethoxy-phenyl)-ethyl)-hexahydroazepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo1.3.4.5- tetrahydro-2H-3-benzazepine, the enantiomers, diastereomers and acid addition salts thereof.
• According to the invention, the new compounds of general formula (I) are obtained by the following methods: a) Reacting a compound of general formula (II) (II) *2 wherein Rx, R2, A, Β, E, m and n are as hereinbefore defined, with a compound of general formula (III) Ζχ - G - R (HI) wherein R and G are as hereinbefore defined and Ζχ represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a me thane sulphonyl oxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group, or a hydroxy group, or Ζχ together with a hydrogen atom of the adjacent methylene group represents an oxygen atom.
If Ζχ represents a nucleophilic leaving group, the reaction is conveniently carried out in a solvent or mixture of solvents such as acetone, diethylether, me thyl formamide, dimethylformamide, dimethyl sulf oxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxan or in an excess of the compounds of general formulae II and/or III used and optionally in the presence of an acid binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, whilst the latter may simultaneously also serve as solvent, or a reaction accelerator such as potassium iodide depending on the reactivity of the nucleophilically exchangeable group, conveniently at temperatures of between 0 and 150"C, preferably at temperatures of between 50 and 120°C, e.g. at the boiling temperature of the solvent used. However the reaction may also be carried out without a solvent. It is, however, particularly advantageous to perform the reaction in the presence of a tertiary organic base or an excess of the amine of general formula (II) used.
If Z1 represents a hydroxy group, the reaction is preferably carried out in a suitable solvent.such as methanol, ethanol, tetrahydrofuran, dioxan, ethyl acetate or glacial acetic acid with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel under a hydrogen pressure of from 2- to 10 bar, preferably 5 bar, and at temperatures of between 20 and 120’C, preferably at temperatures between 50 and 100’C.
If Z1 together with a hydrogen atom of the adjacent methylene group represents an oxygen atom, the reaction is preferably carried out in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxan, ethyl acetate or glacial acetic acid with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel under a hydrogen pressure of from 2 to 10 bar, preferably 5 bar, and at temperatures of between 20 and 120’C, preferably at tenperatures of between 50 and 100’C, or in the presence of a suitable complex metal hydride such as sodium cyanoborohydride in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxan or acetonitrile at temperatures of between 0 and 50’C, but preferably at ambient tenperature. b) Reacting a conpound of general formula (IV) wherein (IV) Rl' R2' j compound A and B are as hereinbefore defxned, wxth a of general formula (V) CH H V®2>/ (V) m and n are defined as hereinbefore* and wherein R, E, G, Z2 represents a nucleophilic leaving group such as a halogen atom or a sulphonyl oxy group, e.g. a chlorine, bromine or iodine atom or a me thane sulphonyl oxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group.
The reaction is preferably carried out in a solvent or mixture of solvents such as methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan in the presence of an acid-binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate an alkali metal amide such as sodium amide or an alkali metal hydride such as sodium hydride, conveniently at temperatures of between 0 and 150°C, preferably at temperatures of between 0 and 50"C. c) In order to prepare compounds of general formula (I) wherein B represents a -CH2- or -CH2CH2- group: reduction of a compound of general formula (VI) R ™ wherein R, R^, R2, A, E, G, m and n are defined as hereinbefore and x represents a -CO- or -CH2CO- group, the carbon atom designated x being linked to the phenyl nucleus.
The reduction is preferably carried out with a metal hydride such as lithium aluminium hydride or diborane or a complex of borane and a thioether, e.g. with borane-dimethylsulphide complex, in a suitable solvent such as diethylether or tetrahydrofuran at temperatures of between 0 and 80"C, but preferably at tempera tures between 10 and 45"C. d) In order to prepare compounds of general formula (I) wherein A represents a -CH2- group and B represents a -CO- or -CH2CO- group: reduction of a conpound of general formula (VII) j _ CH H - 0 - R (Vll) wherein R, Rx, R2, E, G, m and B2 represents a -CO- or -CXH2CO- group, the carbon atom designated x being linked to the phenyl nucleus, with nascent hydrogen.
The reduction is carried out in a suitable solvent such as glacial acetic acid, glacial acetic acid/water or glacial acetic acid/ethanol with nascent hydrogen, e.g. in the presence of zinc/glacial acetic acid, tin/hydrochloric acid or tin dichloride/hydrochloric i are defined as hereinbefore and acid at tenperatures between 20 and 15O’C, but preferably at the boiling tenperature of the reaction mixture, e.g. at tenperatures between 80 and 100’C. e) In order to prepare compounds of general formula I wherein G has the meanings given for G hereinbefore, with the exception of the groups containing a sulphur atom, a sulphinyl or sulphonyl group, and A represents the -CH2-CH2- group and B represents a methylene or carbonyl group: hydrogenation of a conpound of general formula (VIII) wherein R, R1( R2, Β, E, m and n are defined as hereinbefore, G^ has the meanings given for G hereinbefore with the exception of the groups containing a sulphur atom or a sulphinyl or sulphonyl group and B3 represents a "CH,,- or -CO- group.
The hydrogenation is carried out in a solvent or mixture of solvents such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/charcoal, under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar, and at tenperatures of between 0 and 75*C, but preferably at temperatures between 20 and 50’C.
In the reaction described above, any reactive groups present such as hydroxy, amino, alkylamino or imino groups may be protected during.the reaction by means of conventional protecting groups which are cleaved again after the reaction.
For example, a suitable protecting group for a hydroxy group is a t rime thyl silyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group and a suitable protecting group for an amino, alkylamino or imino group is an acetyl, benzoyl, ethoxycarbonyl or benzyl group.
The optional subsequent cleaving of a protecting group is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.
If, according to the invention, a compound of general formula (I) wherein R contains a nitro group is obtained, this can be converted by reduction into a corresponding amino compound of general formula I, or if a compound of general formula I is obtained wherein R contains an amino group, this may be converted by acylation into a corresponding alkanoylamino compound of general formula (I).
The subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, conveniently with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with salts such as iron(II)-sulphate, tin(II) chloride or sodium dithionite or with hydrazine in the presence of Raney nickel at tenperatures of between 0 and 50’C, but preferably at ambient tenperature.
The subsequent acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrile or dimethylformamide, preferably with a reactive derivative of the acid, for exanple with acetyl chloride or acetic anhydride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at tenperatures of between -25"C and 100’C, but preferably at tenperatures of between -10’C and the boiling tenperature of the solvent used.
Since they have at least one chiral centre, the compounds of general formula (I) obtained can be resolved by conventional methods into their diastereomers, for exanple by column chromatography, and into their enantiomers, for exanple by column chromatography on a chiral phase or by crystallisation with optically active acids, e.g. with D- or L-monoraethyl tartaric acid, D- or L-diacetyl tartaric acid, D- or L-tartar±c acid, D- or L-lactic acid or Dor L-camphoric acid.
The compounds of general formula (I) obtained may also be converted into the acid addition salts thereof, particularly for pharmaceutical use into the physiologically acceptable acid addition salts thereof with inorganic or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.
The compounds of general formulae (II) to (VIII) used as starting materials are known from the literature in some cases or may be obtained using methods known per Thus, for example, a starting compound of general formula (II) is obtained by alkylation of a corresponding imino compound of general formula (IV) with a cyclic amine protected at the N atom by a conventional protecting group, said cyclic amine being substituted in the carbon structure by an alkyl group which is in turn substituted in the terminal position by a nucleophilic leaving group, and subsequently cleaving the protecting group used. The cyclic amine required for this is obtained by converting a corresponding cyclic amine substituted by a hydroxyalkyl group into a suitable halogen- or sulphonic acid ester thereof and the imino conpound of general formula (IV) required for this is obtained by cyclising a corresponding conpound, e.g. by cyclising a conpound of general formula (IX) OCH, z 5xoch5 (IX) optionally followed by catalytic hydrogenation and/or reduction of the carbonyl group, for example with sodium borohydride/glacial acetic acid (see EP-A1 0,007,070, EP-A1 0,065,229 and EP-A1 0,109,639).
A compound of general formula (V) used as starting material is obtained by N-alkylation of a corresponding cyclic amine, substituted in the carbon structure by a hydroxyalkyl group, with a corresponding compound or with a corresponding α,ω-dihaloalkane and subsequent reaction with a corresponding HO or HN compound and if necessary subsequent oxidation, a hydroxyalkyl compound thus obtained then being converted into its reactive halogen- or sulphonic acid esters.
A compound of general formulae (VI), (VII) and (VIII) used as starting material is preferably obtained by reacting a corresponding halogen compound with a corresponding amine, optionally followed by the splitting off of protecting groups used to protect amino groups.
As already mentioned hereinbefore, the new compounds of general formula (I) and the physiologically acceptable acid addition salts thereof with inorganic or organic acids have valuable pharmacological properties, particularly a hypotensive effect and an especially long-lasting lowering effect on heart rate and the effect of reducing the 02 requirement of the heart, with only minor side-effects on the.central nervous system.
For example, the following coopounds: A = 3-[(N-(2-(naphth-2-yl)-ethyl)-piperid-3-yl)-methyl] 7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-35 benzazepine-hydrochloride, B = 3-[ (N- (2-(5-methyl-6-methoxy-naphth-2-yl) -ethyl) piperid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine-hydrochloride, C = 3-[2-(N-(2-(6-methoxy-naphth-2-yl)-ethyl)-piperid-2 yl)-ethyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine-hydrochloride, D = 2-[(N-(2- (6-methoxy-naphth-2-yl) -ethyl)-hexahydroazepin-3-yl) -methyl] -6,7-methylenedioxy-1-oxo1,2,3,4-tetrahydro-isoquinoline-hydrochloride, E = 2-[(N-(2-(naphth-2-yl)-ethyl)-hexahydro-azepin-320 yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline-hydrobromide, F = 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperid-3yl)-methyl]-6,7-dimethyl-1,2,3,4-tetrahydro25 isoquinoline-dihydrochloride, G = 2-((N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperid-3yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinol ine-hydrochloride, H = 2-[ (N- (3-(4-methoxy-phenoxy) -propyl) -piperid-3-yl) methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline-hydrochloride, I = 3-[ (N-(4-(thienyl-2)-butyl)-piperid-2-yl)-methyl]7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3benzazepine-hydrochloride, K = 3-[ (Ν-(2-(benzo[b] furyl-2)-ethyl)-piperid-3-yl) methyl] -7, 8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine-hydrochloride and L = 3-[ (N-(2-(benzo[b] thienyl-3)-ethyl)-piperid-3-yl)methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine-hydrochloride were tested for their biological properties as follows: Effect on heart rate in rats: The activity of the test substances on the heart rate was investigated, for each dosage, on 2 rats with an average weight of 250-300 g. The rats were anaesthetised with pentobarbital (50 mg/kg i.p. and 20 mg/kg s.c.) . The test substances were injected in aqueous solution into the jugular vein (0.1 ml/100 g) .
The blood pressure was measured using a cannula inserted in a carotid artery and the heart rate was recorded from an ECG (second or third derivation) derived with needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min) .
The following Table contains the values found: Substance Dosage Lowering of heart Lowering of blood rate in b/m after pressure after in mmHg [mg/kg] 5 min. 20 min. 5 min. 20 min.
A 5.0 - 218 - 259 - 46 - 32 B 5.0 - 188 - 218 - 22 - 15 C 5.0 - 236 - 194 - 40 - 31 D 5.0 - 173 - 123 - 21 - 16 E 5.0 - 169 - 150 - 30 - 16 F 5.0 - 150 - 120 - 49 - 27 G 5.0 - 207 - 101 - 57 - 8 H 5.0 - 190 - 180 - 57 - 33 I 5.0 - 320 - 253 - 65 - 32 K 2.5 - 138 - 156 - 36 L 2.5 - 110 - 163 - 40 - 24 When administered in therapeutic doses the compounds prepared according to the invention show no toxic side effects of any kind. Thus, for exanple when administered intravenously to mice, even in a high dosage of 20 mg/kg, substances A and L showed no toxic side effects apart from a slight sedation.
In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prevention and treatment of ischaemic heart disease.
The dosage required to achieve this effect is conveniently from 0.01 to 0.2 mg/kg of body weight, preferably from 0.03 to 0.15 mg/kg of body weight, once or twice a day. The conpounds of general formula I and the physiologically acceptable acid addition salts thereof with inorganic or organic acids produced according to the invention may be incorporated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with com starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, carboxymethyl- cellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories.
The following Examples are intended to illustrate the invention: Examples A-K relate to preliminary products.
Example A 2-Γ(Piperid-3-yl) -methyl! -6.7-dimethoxv-l-oxo-l.2.3.4tetrahydro- isocruinoline a) N-Benzvl-3-(hydroxymethyl)-piperidine A mixture of 40.3 g (0.35 mol) of 3-(hydroxymethyl)piperidine, 97.4 ml (0.70 mol) of triethylamine and 40.3 ml (0.35 mol) of benzyl chloride is heated to 95’C within 30 minutes and kept at this temperature for 2 hours. The reaction mixture is cooled down and dissolved in a mixture of 2 molar sodium hydroxide solution and ethyl acetate. The organic phase is washed with water, separated off, dried over magnesium sulphate and evaporated down in vacuo.
Yield: 57.2 g (79.6% of theory)» Rf value: 0.45 (aluminium oxide, neutral, eluant: 3% ethanol in methylene chloride). b) N-Benzyl-3-(benzenesulphonyloxymethyl)-piperidine A mixture of 6.8 g (0.033 mol) of N-benzyl-3-(hydroxymethyl)-piperidine, 6.7 ml (0.052 mol) of benzenesulphonic acid chloride, 50 ml of 20% aqueous sodium hydroxide solution, 100 ml of toluene and 1 spatula tip of tetrabutyl ammonium bromide is stirred for 3 hours at ambient temperature. The mixture is then diluted with 250 ml of ethyl acetate and the organic phase is washed with water. The organic phase is separated off, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Yield: 9.4 g (92% of theory), Rf value: 0.5 (silica gel, eluant: methylene chloride). % ethanol in c) 2- Γ (N-Benzyl-nicerid-3-yl) -methyl! -6.7-dimethoxyl-oxo-l. 2.3.4-tetrahydro-isoquinoline .2 g (0.025 mol) of 6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline are dissolved in 70 ml of dimethylsulphoxide and 3.1 g (0.025 mol) of potassium tert.butoxide are added with stirring. After half an hour, 9.3 g (0.0275 mol) of N-benzyl-3(benzenesulphonyloxymethyl)-piperidine in 20 ml of dimethylsulphoxide-are added to the resulting potassium salt suspension and the mixture is stirred for 2 hours at 40°C. It is then poured onto ice water and extracted three times, each time with 120 ml of ethyl acetate.
The combined organic phases are washed with water, dried over magnesium sulphate and evaporated down in vacuo.
The residue obtained is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 2%).
Yield: 7.7 g (78.5% of theory), Rf value: 0.5 (silica gel, eluant: 5% ethanol in methylene chloride and 1 drop of ammonia). d) 2-Γ(Piperid-3-yl)-methyl!-6.7-dimethoxy-l-oxo1.2.3.4-tetrahydro-isoquinoline 9.4 g (0.0238 mol) of 2-[ (N-benzyl-piperid-3-yl) methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydroisoquinoline are hydrogenated in 200 ml of methanol in the presence of 2 g of 20% palladium hydroxide/charcoal for 3 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated to dryness in vacuo.
Yield: 7.2 g (99% of theory), Rf value: 0.15 (silica gel, eluant: 10% ethanol in methylene chloride and 1 drop of ammonia).
Example £ 3-Chloromethyl--Ν- Γ3- (naphthyl-2-oxy) -propyll -piperidine a) 3- (Hydroxymethyl) -Ν- Γ3- (naphthyl-2-oxv) -propvll piperidine A mixture of 11.5 g (0.2 mol) of 3-hydroxymethylpiperidine and 11 g of 2-(3-chloropropoxy)-naphthalene is heated to 120°C-for 1 hour. The residue is purified over silica gel (0.063 - 0.2 mm) with ethyl acetate/ethanol/ammonia = 90:10:1.
Yield: 11.5 g (76.6% of theory), Melting point: 99-101"C. b) 3-Chloromethyl-Ν-Γ3-(naphthyl-2-oxy)-propyll piperidine A solution of 1.5 g (5 mmol) of 3-(hydroxymethyl)20 N-[3-(naphthyl-2-oxy)-propyl]-piperidine in 25 ml of chloroform is mixed with 1.5 ml of thionyl chloride and refluxed for 1½ hours. The mixture is evaporated to dryness ia vacuo. The residue is taken up in methylene chloride, washed with water, 2 molar sodium hydroxide solution and again with water. After the methylene chloride phase has been dried over magnesium sulphate it is evaporated down ia zacHQ.
Yield: 1.4 g (87.5% of theory), Rf value: 0.8 (silica gel, eluant: ethyl acetate/ethanol/ammonia = 90:40:2).
Example C 2-f(Hexahydro-azepin-3-yl)-methyl! -6.7-methvlenedioxy1-oxo-l. 2.3.4-t-.etrahydro-isoquinoline a) N-Benzyl-caprolactam 33.9 g (0.3 mol) of caprolactam are dissolved in 250 ml of dimethylsulphoxide and 37 g (0.33 mol) of potassium tert .butoxide are added with stirring. The reaction temperature rises to 60*C. It is stirred for half an hour at 60eC and then 35 ml (0.3 mol) of benzyl bromide are added dropwise. After another 2¼ hours at 60"C it is poured onto 1 litre of ice water and extracted three times with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate and evaporated down in vacuo.
Yield: 60.3 g (99% of theory), Rf value: 0.6 (silica gel, eluant: 5% ethanol in methylene chloride). b) 1-Benzyl-caprolactam-3-carboxylic acid 180 ml of 2.6 molar butyllithium solution in n-hexane are added at -60"C, with stirring and under nitrogen, to 33.9 g = 47.1 ml (0.33 mol) of diisopropylamine in 450 ml of absolute ether. Then, while cooling is continued, 48.8 g (0.24 mol) of N-benzyl-caprolactam dissolved in 150 ml of absolute ether are added dropwise. After stirring for 10 minutes, the cooling bath is removed and carbon dioxide is piped in for 15 minutes. The reaction mixture is poured onto ice, the ethereal phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The aqueousalcoholic phases are combined, extracted with ether, acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined methylene chloride phases are dried over magnesium sulphate and the solvent is distilled off in vacuo. Yield: 15.7 g (26.5% of theory), IR spectrum (methylene chloride): 1735 and 1600 cm-1 (CO) . c) 1 -Benzyl - 3-hydroxymethyl - hexahydro-azepine 14.8 g (0.06 mol) of 1-benzyl-caprolactam-3-carboxylic acid dissolved in 300 ml of absolute tetrahydrofuran are added dropwise to 6.84 g (0.28 mol) of lithium aluminium hydride in 300 ml of absolute tetrahydrofuran. Then the mixture is refluxed for 6 hours, then 6.8 ml of water, 6.8 ml of 2 molar sodium hydroxide solution and 21 ml of water are added whilst cooling with ice water. The precipitate is suction filtered, washed with tetrahydrofuran and the filtrate is evaporated down in' vacuo. The residue is purified by column chromatography over aluminium oxide N (activity II, eluant:.methylene chloride).
Yield: 8.4 g (63.8% of theory), IR spectrum (methylene chloride): 3620 cm-1 (OH). d) 1-Benzyl-3-(4-toluenesulphonyloxymethyl)-hexahydroazepine g (0.0684 mol) of 1-benzyl-3-hydroxymethyl-hexahydroazepine are dissolved in 150 ml of pyridine and 14.3 g (0.075 mol) of p-toluenesulphonic acid chloride are added with stirring and the resulting mixture is stirred for 1 hour at ambient temperature. It is evaporated down in vacuo, taken up in methylene chloride and washed with 2 molar sodium hydroxide solution and water. After drying over magnesium sulphate the organic phase is evaporated down in vacuo.
Yield: 23.3 g (91.3% of theory), Rf value: 0.45 (silica gel, eluant: 5% ethanol in methylene chloride). e) 2-Γ(N-Benzyl-hexahydro-azepin-3-yl)-methyl!-6.7methylenedioxy-1-oxo-l. 2.3.4-tetrahydro-isocniinolinA 7.4 g (0.0387 mol) of 6,7-methylenedioxy-l-oxo1,2,3,4-tetrahydro-isoquinoline are dissolved in 100 ml of dimethylsulphoxide, 4.5 g (0.04 mol) of potassium tert.butoxide are added and the mixture is stirred for half an hour at ambient tenperature. Then 16.8 g (0.044 mol) of l-benzyl-3-(4-toluenesulphonyloxymethyl)hexahydro-azepine are added and the mixture is stirred for 3 hours at ambient tenperature. The reaction mixture is dissolved in ethyl acetate and extracted twice with water. The organic phase is dried over magnesium sulphate and evaporated down in vacuo. The residue is purified over aluminium oxide N (activity II, eluant: methylene chloride, methylene chloride + 2% ethanol).
Yield: 3.0 g (19.6% of theory), Rf value: 0.6 (silica gel, eluant: 5% ethanol in methylene chloride). f) 2-f(Hexahydro-azepin-3-yl)-methyl!-6.7methylenedioxy-l-oxo-1.2.3.4-tetrahydro-iTsoquinol ine 6.7 g (0.017 mol) of 2- [ (N-benzyl-hexahydro-azepin-3yl)-methyl]-6,7-methylenedioxy-1-oxo-l,2,3,4-tetrahydroisoquinoline are hydrogenated in 250 ml of methanol in the presence of 2 g of 20% palladium hydroxide/charcoal for 4 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated down to dryness in vacuo. The residue is crystallised from acetone. Yield: 4.9 g (95% of theory), M.p.: 267-269eC.
ExamplaJQ 3-Chloromethyl-N- Γ3- (naphthyl-2-oxy) -oropvll -hexahvdroazepine a) 3-Hydroxymethyl-hexahydro-azepine 16.6 g (0.0757 mol) of 1-benzyl-3-hydroxymethyl hexahydro-azepine are hydrogenated in 500 ml of methanol in the presence of-16.6 g of 20% palladium hydroxide/charcoal for 2 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated down in vacuo.
Yield: 8 g (81.8% of theory), Rf value: 0.5 (silica gel, eluant: methylene chloride/ ethanol/ammonia = 5:4:1). b) 3-Hydroxymethyl-N- Γ3- (naphthyl-2-oxv) -propvll hexahydro-azepine-hydrpchlQEida A mixture of 7.8 g (0.06 mol) of 3-hydroxymethylhexahydro-azepine and 6.7 g (0.03 mol) of 2-(3chloropropoxy)-naphthalene is heated for 1 hour to 120"C. The reaction mixture is purified over silica gel (0.063 - 0.2 mm) with ethyl acetate/ethanol/ ammonia 90:10:1.
Yield: 2.3 g (24.3% of theory), Melting point: 127-129eC. c) 3 "Chloromethyl·-N- f3^(naphthyl-2 -.QxyJ.rj?£ppyJLl— hexahydro-azepine 2.4 g .(6.86 mmol) of 3-hydroxymethyl-N-[3-(naphthyl2-oxy)-propyl]-hexahydro-azepine hydrochloride dissolved in 30 ml of chloroform are mixed with 5 ml of thionyl chloride and refluxed for 1 hour. The mixture is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride, and extracted with water, 2 molar sodium hydroxide solution and-again with water. The methylene chloride phase is dried over magnesium sulphate and evaporated down in vacuo.
Yield: 1.1 g (48.5% of theory), Rf value: 0.55 (silica gel, eluant: 5% ethanol in methylene chloride).
ExamplS-E 2- f (Pvrrolid-3-yl) -methyl! -6.7-dimethoxy-l-oxo-l.2.3.4tetrahydro-isoquinoline a) Ν-Benzyl - 2 -pyrrolidone 14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil is added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide. The mixture is then stirred for 5 hours at 40 to 50°C and, at 25 to 30"C, 56.4 g = 39.2 ml (0.33 mol) of benzyl bromide are added dropwise. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated ia vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol. Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride). b) N-Benzyl-2-pyrrolidone-3-carboxylic acid 150 ml of 1.6 molar butyllithium solution in n-hexane are added with stirring and under nitrogen at -60*C to 28.3 g = 39.3 ml (0.28 mol) of diisopropylamine in 400 ml of absolute ether. 35.1 g (0.2 mol) of N-benzyl-2-pyrrolidone dissolved in 150 ml of absolute ether are added dropwise thereto at -60"C. The cooling bath is removed and dry carbon dioxide is introduced for 15 minutes. After stirring for 10 minutes, the mixture is poured onto ice, the organic phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid whilst being cooled. The aqueous phase is extracted twice with methylene chloride and after the organic phase has been dried over magnesium sulphate it is evaporated down in vacuo.
Yield: 35 g (79.8% of theory), Rf value: 0.42 (silica gel, eluant: 5% ethanol in methylene chloride). c) N-Benzyl - 3 -hydroxymethyl -pyrrol idine g (0.16 mol) of N-benzyl-2-pyrrolidone-3-carboxylic acid dissolved in 250 ml of absolute tetrahydrofuran are added dropwise, with stirring to 12.2 g (0.32 mol) of lithium aluminium hydride in 350 ml of absolute tetrahydrofuran. After refluxing for 6 hours, 18.2 ml of water, 12.2 ml of 15% aqueous sodium hydroxide solution and 36.6 ml of water are added whilst cooling with ice water. The precipitate formed is suction filtered and washed with tetrahydrofuran. The combined filtrates are evaporated down In vacuo and the residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and then with increasing amounts of ethanol (up to 2%) .
Yield: 16 g (52.3% of theory), Rf value: 0.42 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride) . d) 3- (Benzenesulphonyloxymethyl)-1-benzvl-Pvrrolidine. ml of 20% sodium hydroxide solution are added dropwise, for a period of 1 hour, to a mixture of 3.8 g (20 mmol) of N-benzyl-3-hydroxy-pyrrolidine and 3.7 ml (24 mmol) of benzenesulphonic acid chloride. 150 ml of toluene are added, the organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness in vacuo.
Yield: 5.9 g (89.4% of theory), Rf value: 0.4 (silica gel, eluant: 5% ethanol in methylene chloride). e) 2- ΓΝ- (Benzyl-pyrrolid-3-yl) -methyl! -6.7-dimethoxyl-oxo-l. 2.3.4-tetrahydro-isoquinoline 3.3 g (15.9 mmol) of 6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline are dissolved in 50 ml of dimethylsulphoxide and combined with 2 g (17.5 mmol) of potassium tert.butoxide with stirring at ambient temperature. After half an hour, 5.8 g (17.5 mmol) of 3-(benzenesulphonyloxymethyl)-1-benzyl-pyrrolidine in 10 ml of dimethylsulphoxide are added to the resulting potassium salt suspension and the mixture is stirred for 3 hours at 60°C. It is poured onto ice water and extracted with ethyl acetate. The combined organic phases are washed with water and dried over magnesium sulphate. The organic phase is evaporated down in vacuo and the residue obtained is purified over 350 g of aluminium oxide N (activity II) with methylene chloride and then with increasing quantities of ethanol (up to 1%) .
Yield: 3.3 g (54.4% of theory), Rf value: 0.74 (aluminium oxide N, eluant: 5% ethanol in methylene chloride). f) 2-Γ(Pyrrolid-3-yl)-methyl!-6.7-dimethoxy-l-oxo1.2.3.4-tetrahydro-isoquinoline 3.2 g (8.4 mmol) of 2-[(N-benzyl-pyrrolidyl)-methyl]6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline are dissolved in 250 ml of methanol and hydrogenated in the presence of 1 g of 20% palladium hydroxide/charcoal for 3 hours at ambient temperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated to dryness in vacuo. The residue is purified over 150 g of silica gel (0.063 0.2 mm) with methylene chloride/ ethanol/ammonia = 6:1:0.5.
Yield: 0.9 g (37.5% of theory), Rf value: 0.6 (silica gel, eluant: methylene chloride/ ethanol/ammonia = 5:4:1).
Example F 3-(p-Toluenesulphonyloxymethyl)-Ν-Γ2-(6-methoxvnaphth-2-yl)-ethyl!-pyrrolidine a) 3-Hydroxymethyl-pyrrolidine g (0.073 mol) of N-benzyl-3-hydroxymethyl-pyrrolidine are hydrogenated for 7 hours at 50"C and under 5 bar in 300 ml of methanol and in the presence of 1.5 g of 20% palladium hydroxide/activated charcoal. The catalyst is then removed by suction filtering and the filtrate is evaporated down in vacuo.
Yield: 7.3 g (99% of theory), Mass spectrum: molecular peak 101. b) 3-Hydroxymethyl-Ν-Γ2-(6-methoxy-naphth-2-yl)ethyl!-pyrrolidine A mixture of 3.6 g (29.4 mmol) of 3-hydroxymethylpyrrolidine and 4.7 g (14.7 mmol) of 2-(2-bromoethyl)6-methoxy-naphthalene is heated to 120*C for 2 hours.
The reaction mixture is purified over 200 g of silica gel (0.063 - 0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Yield: 3.48 g (82.5% of theory).
Melting point: 121-123"C. c) 3- (p-Toluenesulphonyloxvmethvl) -N- Γ2- (6-methoxynaphthalene-2) -ethy] 1 -pyrrolidine 0.8 g (2.8 mmol) of 3-hydroxymethyl-N-[2-(6-methoxynaphth-2-yl)-ethyl]-pyrrolidine are dissolved in 10 ml of pyridine and 1.2 g (€.3 mmol) of p-toluenesulphonic acid chloride are added with stirring. After 2 hours at ambient temperature the mixture is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride, washed with 2 molar sodium hydroxide solution and water. The organic phase is then dried over magnesium sulphate and evaporated down in vacuo. The residue is purified over 150 g of silica gel (0.063 0.2 mm) with ethyl acetate and then with increasing amounts of ethanol.
Yield: 0.6 g (48.8% of theory), Rf value: 0.45 (silica gel, eluant: 5% ethanol in methylene chloride).
Bacample-S 2-Γ (Azacyclooctyl-3)-methyll -6.7-dimethoxv-l-oxo1.2.3.4-tetrahydro-isoquinoline a) 1-Benzyloxy-azacyclooctane g (0.196 mol) of 2-azacyclooctanone are dissolved in 150 ml of dimethylsulphoxide and combined, with stirring, with 24.2 g (0.216 mol) of potassium tert.butoxide and stirred for half an hour at 40°C.
Then 24 ml (0.2 mol) of benzylbromide are added dropwise over a period of a quarter of an hour, during which time the temperature rises to 80°C. The mixture is stirred for 2 hours, during which the reaction temperature falls back to ambient temperature. The reaction mixture is poured onto 1 litre of ice water and extracted 4 times, each time with 150 ml of ethyl acetate. The combined organic phase is washed with water, dried over magnesium sulphate and evaporated down in vacuo.
Yield: 42.7 g (100% of theory), Rf value: 0.55 (silica gel, eluant: 5% ethanol in methylene chloride). b) 1-Benzyl-azacylooctane-2-oxo-3-carboxylic acid 147 ml of 1.6 molar butyl lithium solution in n-hexane are added dropwise at -60eC, with stirring and under nitrogen, to 26.7 g = 38.4 ml (0.26 mol) of diisopropylamine in 250 ml of absolute ether. Then at -60C, 42.7 g (0.196 mol) of 1-benzyl-2-oxoazacyclooctane in 100 ml of absolute ether were added dropwise thereto. After 10 minutes, dry carbon dioxide was introduced for 20 minutes. The reaction mixture is poured onto ice, the ethereal phase is separated off and extracted twice with 2 molar sodium hydroxide solution. The combined aqueous phases are extracted once with ether and then acidified with concentrated hydrochloric acid, whilst being cooled. The mixture was extracted 3 times with methylene chloride, and the methylene chloride phase is dried over magnesium sulphate and evaporated down ia vacuo.
Yield: 25.9 g (50.6% of theory), Rf value: 0.15 (aluminium oxide, eluant: 5% ethanol in methylene chloride).
C) 1-Benzyl-3-hydroxymethyl-azacyclooctane 53.6 g (0.205 mol) of l-benzyl-2-oxo-azacyclooctane3-carboxylic acid dissolved in 100 ml of absolute tetrahydrofuran is added dropwise with stirring to 22.7 g (0.6 mol) of lithium aluminium hydride in 800 ml of absolute ether. After refluxing for half an hour, the mixture is combined with 28.4 ml of water, 19 ml of 15% sodium hydroxide solution and 57 ml of water, whilst cooling with ice water. The precipitate formed is suction filtered and washed with tetrahydrofuran. The combined filtrates are evaporated down in vacuo and the residue obtained is purified over 700 g of aluminium oxide (neutral, activity II) with 1% ethanol in methylene chloride.
Yield: 9.3 g (19.6% of theory), Rf value: 0.5 (silica gel, eluant: 5% ethanol in methylene chloride) . d) l -Benzyl - 3 - chloromethyl - azacvclooctane 9.3 g (39.8 mmol) of l-benzyl-3-hydroxymethyl-azacyclooctane are combined in 30 ml of pyridine with 10 ml (79.6 mmol) of benzenesulphqnic acid chloride and stirred for 2½ hours at ambient temperature. The reaction mixture is evaporated down In vacuo. The residue remaining is dissolved in 150 ml of methylene chloride, then washed with 2N sodium hydroxide solution and water. The organic phase is dried over magnesium sulphate, evaporated to dryness and purified over 150 g of silica gel (0.063- 0.2 mm) with methylene chloride. Yield: 3.5 g (35% of theory) Rf value: 0.75 (silica gel, eluant: 5% ethanol in methylene chloride). e) 2- f (N-Benzyl-azacyclooct-3-yl) -methyl! -6.7-dimethoxvIzdxo- 1.. 2a tetrahydro-isoquinoline 2.3 g (11.1 mmol) of 6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline are dissolved in 40 ml of dimethylsulphoxide and 1.33 g (12.2 mmol) of potassium tert-butoxide are added with stirring. After half an hour, 3.5 g (9.4 mmol) of 1-benzyl-3-chloromethylazacyclooctane in 40 ml of dimethylsulphoxide are added to the resulting potassium salt suspension and the mixture is stirred for 2½ hours at 120*C. It is poured onto ice water and extracted 3 times, each time with ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate and evaporated down in vacuo. The residue obtained is purified over 150 g of silica gel (0.063-0.2 mm) with 1% ethanol in methylene chloride.
Yield: 1 g (25.1% of theory), Rf value: 0.5 (silica gel, eluant: 2% ethanol in methylene chloride). f) 2rl(AaacyclPQCt=3-yl) -methyl 1 -6-. 7.-dimethoxy-1oxo-l.2.3.4-tetrahydro-isoquinoline 0.85 g (2 mmol) of 2-[ (N-benzyl-azacyclooctyl-3) methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4-tetrahydroisoquinoline are hydrogenated in 50 ml of methanol in the presence of 0.85 g of 20% palladium hydroxide/charcoal for 4½ hours at ambient tenperature under 5 bar of hydrogen. The catalyst is then removed by suction filtering and the filtrate is evaporated to dryness.
Yield: 0.5g (74.6% of theory), Rf value: 0.45 (silica gel, eluant: 25% ethanol in methylene chloride and 1 drop of ammonia) Example,. H 1-Chloro-3- (4.?methoxyrM=mathylamino-phenyl) -propane g (0.073 mol) of N-methyl-4-methoxy-aniline are dissolved in 50 ml of dimethyl sulphoxide and 9 g (0.08 mol) of potassium tert .butoxide are added with stirring. After half an hour, 10 ml of l-bromo-3chloropropane are added and the mixture is stirred for 3 hours at ambient tenperature. It is poured onto ice water, extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness. The residue is purified over silica gel (0.063 - 0.2 mm) with methylene chloride.
Yield: 9.1 g (58.3% of theory), Rf value: 0.55 (silica gel, eluant: methylethyl ketone/xylene = 1:6) Calculated: C 61.82 H 7.55 N 6.55 Cl 16.59 Found: 61.71 7.88 6.69 16.24.
Example. I - Γ (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methvl! 5.6-methylenedioxy-phthalimide 2.1 g (0.011 mol) of 5,6-methylenedioxy-phthalimide are dissolved in 100 ml of dimethylsulphoxide and 1.25 g (0.012 mol) of potassium tert.butoxide are added with stirring. The potassium salt is precipitated. It is stirred for a further Ji hour at ambient temperature, a solution of 2.5 g (0.01 mol) of 3-chloromethylN-(3-(pyrid-3-yl)-propyl)-piperidine in 20 ml of dimethylsulphoxide is added and the mixture is heated to 120"C for 8 hours. It is poured onto ice water, extracted three times, each time with 150 ml of ethyl acetate, and after drying over magnesium sulphate, the organic phase is evaporated down in vacuo. The residue is purified over 200 g of silica gel (0.063 - 0.2 ram) with ethyl acetate/ethanol/ ammonia - 80:10:0.5.
Yield: 3 g (74% of theory), Calc. (2 x HCl) C 55.42 H 5.86 N 8.43 Cl 14.22 Found: 55.28 6.06 8.26 14.64 Example K 2- ΓΝ- (3-Chloropropyl·) -piperid-3-yl-methyl! -6.7dimefchQxy.-1-oxo-l. 2,3.4-tetrahyflrQrigpqninpline. g (0.01 mol) of 2-[(piperid-3-yl)-methyl]-6,7dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline are dissolved in 50 ml of dimethylsulphoxide and 1.3 g (0.011 mol) of potassium tert.butoxide are added with stirring. After half an hour, 3 ml of l-bromo-3chloro-propane are added and the mixture is stirred for hour at ambient temperature. It is poured into ice water, extracted with ethyl acetate, and the organic phase is washed with water, dried over sodium sulphate and evaporated to dryness in vacuo.
Yield: 2.7 g (71% of theory), Rf value: 0.65 (silica gel, eluant: ethyl acetate/ethanol/ ammonia = 50:45:5).
Example, 1 2- Γ (Ν- (3- (Naph«--h-2-yl) -propyl) -piperid-3-vl) -methyl! 6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahydro-isoquinoliner hydrochloride A mixture of 1 g (3.2 mmol) of 2-(piperid-3-yl-methyl)6,7 -dimethoxy-1 - oxo-1,2,3,4- tetrahydro- isoquinoline, ml of dimethylsulphoxide, 0.5 g (0.36 mmol) of potassium carbonate and 0.75 g (3.66 mmol) of 2(3-chloropropyl) -naphthalene is heated to 120"C for 3 hours. The reaction mixture is poured onto ice water and extracted three times, each time with 50 ml of ethyl acetate. The combined organic phases are washed with 2 molar sodium hydroxide solution and water, dried over magnesium sulphate, evaporated down in vacuo and the residue obtained is purified over silica gel (0.063 0.2 mm) with 1% ethanol in methylene chloride. The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid and recrystallised from acetone.
Yield: 0.74 g (44% of theory), Melting point: 179-181"C Calculated: C 70.77 H 7.37 N 5.50 Cl 6.96 Found: 70.47 7.40 5.47 7.06.
Example 2. 2-J (N- (3 -INaBhtAyl.-2-Qxy)..-jgEQpyJLL-p.iperid=.3-yJL) -. methyl! -6. 7-dimethyl-l-QXQrl^ 2,3 .,4-_tet rahydro _ isoquinoline-hydrochloride 1.58 g (9 mmol) of 6,7-dimethyl-1-oxo-l,2,3,4tetrahydro-isoquinoline are dissolved in 30 ml of dimethylsulphoxide and 1.1 g (9.9 mmol) of potassium tert.butoxide are added with stirring. After 1 hour, a solution of 2.9 g (9.1 mmol) of 3 - chloromethyl-N-[3(naphthyl- 2-oxy)-propyl]-piperidine in 10 ml of dimethylsulphoxide is added and the reaction mixture is stirred for 16 hours at 80’C. It is then poured onto ice water, extracted 3 times, each time with 50 ml of ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and, after evaporation, purified on silica gel (0.63 - 0.2 mm) with ethyl acetate/ethanol/ammonia = 95:5:0.5. The hydrochloride is obtained as a hydrate from a solution in acetone using ethereal hydrochloric acid.
Yield: 2 g (45.1% of theory), Melting point: 152-154eC Calculated: C 70.50 H 7.69 N 5.49 Cl 6.93 Found: 70.31 7.52 5.49 7.10 Example 3 2-1 (IL· (.3.- (Naphth-2-yl).-pEopyl) -piperidr3. =xL) rmethyll 6.7-dimethyl-l.2.3.4-tetrahydro-isoquinoline-dihvdro20 .chloride 0.8 g (18 mmol) of 2-[(N-(3-(naphth-2-yl)-propyl)piperid-3-yl)-methyl!-6,7-dimethyl-1-oxo-l,2,3,4tetrahydro-isoquinoline are dissolved in 10 ml of absolute tetrahydrofuran and 20 ml of absolute ether, mg (18 mmol) of lithium aluminium hydride are added and the mixture is refluxed for 1 hour. The reaction mixture is decomposed by the addition of 5 ml of saturated aqueous sodium sulphate solution, filtered to remove the sodium sulphate precipitated and washed with tetrahydrofuran. The filtrate is dried over magnesium sulphate and after evaporation, purified over 150 g of silica gel (0.063 - 0.2 mm) with ethyl acetate/ethanol/ammonia = 90:10:0.05. The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid.
Yield: 0.49 g (54.4% of theory).
Melting point: 148-150"C - 58 Calculated: C 69.61 H 8.18 N 5.41 Cl 13.70 Found: 69.46 8,32 5.26 14.17 Example, 4 2- i (Nz 1.3-(.Pyrid-3-yl) -propyl) Tpiperid-3-yl) -methyl.] 5«S-methyleneaioxy-J.Tpxo-l.J-dihydrQ-ispindQlex dihydrochJLQ.ride 2.4 g (5.9 mmol) of 2-[ (N-(3-(pyrid-3-yl)-propyl) piperid-3-yl) -methyl] -5,6-methylenedioxy-phthalimide are dissolved in 50 ml of glacial acetic acid and refluxed for 5 hours. At intervals of 1 hour, 1 g batches of zinc powder are added. After the reaction time has ended, the mixture is suction filtered and evaporated with ethanol. The residue is dissolved in methylene chloride, extracted with concentrated ammonia, dried over magnesium sulphate and after evaporation in vacuo purified over 150 g of silica gel (0.063 - 0.2 mm) ethyl acetate/ethanol/ammonia = 90:10:0.2. The hydrochloride is precipitated from a solution in acetone.
Yield: 2.05 g (75% of theory), Melting point: 165-167"C Calculated: C 59.22 H 6.27 N 9.00 Cl 15.20 Found: 59.03 6.45 8.85 15.06 Example 5 3- f (N- (3- (Pyrid-3-vl) -nropyl) -pyrrol id-3-yl) -methyl 1 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3benzoazepine-dihydrochloride 1.1 g (2.6 mmol) of 3-((N-(3- (pyrid-3-yl)-propyl)pyrrol id-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l,3-dihydro2H-3-benzoazepine, dissolved in 50 ml of ethanol, are hydrogenated in the presence of 1 g of 10% palladium on activated charcoal at 80"C and under 5 bar of hydrogen for 2 hours. Then the catalyst is removed by suction filtering and, after being evaporated down in vacuo. the filtrate is purified over 100 g of silica gel (0.063 0.2 mm) with ethyl acetate/ethanol/ammonia =*80:40:1.
The hydrochloride is precipitated from a solution in acetone.
Yield: 0.37 g (33% of theory).
Melting point: 96-98’C Calculated: C 60.42 H 7.11 N 8.46 Cl 14.28 Found: 60.35 7.46 8.43 14.58 Example. 6 3- ί (N- (3- (Indolyl-3)-propyl) -hexahvdro-azepinvl-3) methyl 1 -7.8-dimethoxy-1.3.4.5-tetrahvdro-2H-3frenzazepine-flihyflrpchlQride- monohydrate Prepared from 3-[(N-(3-(indolyl-3)-propyl)-hexahydroazepinyl-3)-methyl]-7,8-dimethoxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Example 3.
Yield: 53% of theory.
Melting point: 158-160’C Calculated: C 63.58 H 8.00 N 7.41 Cl 12.51 Found: 63.41 8.18 7.36 12.23 Example 7 2-r (N- (2- (4-Amino-phenvl)-ethyl) -piperid-3-vl) ^methvll 5.6-dimethoxy-l-oxo-l.3-dihydro-isoindoledihydrechlorifle 2.1 g (4.78 mmol) of 2-[(N-(2-(4-nitro-phenyJ)ethyl) -piperid-3-yl) -methyl] -5,6-dimethoxy-1-oxo1,3-dihydro-isoindole are dissolved in 50 ml of glacial acetic acid and 0.4 ml (8.22 mmol) of hydrazine hydrate and 1 spatula tip of Raney nickel are added with stirring. The addition of 0.2 ml of hydrazine and 1 spatula tip of Raney nickel is repeated 3 times at intervals of 1 hour. The catalyst is removed by suction filtering, the residue is washed with methanol, the filtrate is dried with magnesium sulphate, evaporated down in vacuo and the residue obtained is purified over aluminium oxide (neutral, activity II) with methylene chloride and then with increasing quantities.of ethanol. Yield: 1.8 g (91.8% of theory), g is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid.
Yield: 1.02 g (86.4% of theory based on the base), Melting point: 232-235’C Calculated: C 59.72 H 6.89 N 8.71 Cl 14.69 Found: 59.54 7.08 8.56 14.45 Example 8. 2-.ΠΝ- (2- (4-Acet amino--phenyl) --ethyl) -piperid-3. zy 3D methyll -5.6-dimethoxy-l-oxo-l.3-dihydro-isoindole 819 mg (2 mmol) of 2-[(N-(2-(4-amino-phenyl)-ethyl)piperid-3-yl)-methyl]-5,6-dimethoxy-l-oxo-l,3-dihydroisoindole are mixed with 10 ml of methylene chloride and after the addition of 0.3 ml (2.2 mmol) of .25 triethylamine, 0.16 ml (2.2 mmol) of acetyl chloride are added dropwise. The reaction temperature rises to 30°C. The mixture is stirred for half an hour at ambient temperature, extracted twice with water, the organic phase is dried over magnesium sulphate and evaporated down In vacuo. The residue is crystallised from acetone.
Yield: 660 mg (73.2% of theory), M.p.: 195-196’C Calculated: C 69.16 H 7.37 N 9.31 Found: 69.33 7.11 9.16 Example 9 - Γ (Ν- (3 - (Furvl-2) -propyl) -pioerid-3-vl) -methyl 1 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine hydrochloride 3.2 g (0.010 mol) of 3-[(piperid-3-yl)-methyl]-7,8dimethoxy- 2 -oxo-1,3,4,5 - tetrahydro- 2H-3 -benzazepine are hydrogenated in 100 ml of absolute ethanol in the presence of 1.3 g (0.010 mol) of 3-(furyl-2)-propanal and 1 g of Raney nickel at 80eC for 2 days under 5 bar. The catalyst is removed by suction filtering; the filtrate is evaporated down and purified over a silica gel column with methylene chloride/methanol as eluant. The hydrochloride is precipitated with ethereal hydrochloric acid and crystallised from acetone.
Yield: 0.50 g (11% of theory).
Melting point: 204-206"C Calculated: C 64.85 H 7.62 N 6.05 Cl 7.66 Found: 64.88 7.76 5.93 7.55 Rf value: 0.69 (silica gel; methylene chloride/methanol = 10:1; ammonia/atmosphere) Example„-1Q 2- Γ (N- (3? (j-Methylpheaoxy) -propyD -piperid-l-y2J methyl) -6.7 - dimethoxy-1.2.3 ._4-tetrahydro-isoquinolinedihydrochloridfi Prepared from 2-[ (N- (3-(3-methylphenoxy) -propyl) piperid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Exanple 3.
Yield: 92.9% of theory, Melting point: 100-103eC Calculated: C 61.23 H 7.99 N 5.29 Cl 13.39 Found: 61.21 .8.13 5.10 13.15 Example n 2ζί,ίΧί^ί3-(Naphthyl =J2.T.oxy)-=prppyl) Tgyrr,olid,-3-yl) methyl 1-6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahydroisocruinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-chloromethyl-N-[3-(naphthyl2-oxy) -propyl] -pyrrolidine analogously to Example 2. Yield: 22% of theoiy, Melting point: 78-80’C Calc, (x H2O): C 65.83 H 7.04 N 5.29 Cl 6.70 Pound: 65.79 7.00 5.03 6.99 Example. 12 - Γ (N- (3- (Naphthyl-2-oxy) -propyl)-pvrrolid3,=yll -methyl 1.- 6., 7.-methylenedioxy-1-qxq- 1,2,2. ..4tetrahydEOzj.aQfipiinoline-hydEP.chlQride Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline and 3 - chloromethyl-N-[3(naphthyl-2-oxy) -propyl] -pyrrolidine analogously to Example 2.
Yield: 53% of theory.
Melting point: 78-80’C Calc, (x H2O): C 65.56 H 6.48 N 5.46 Cl 6.91 Found: 65.44 6.32 5.38 7.13 Example 13 2-f (N- (2-(Naphth-2-yl) -ethyl) -pyrrolid-3-yl) -methyl 1 6.7-dimethoxy-l. 2.3.4-tetrahydro-isoquinolinehydrochloride Prepared from 2-((N-(2-(naphth-2-yl)-ethyl)-pyrrolid-3yl)-methyl]- 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in tetrahydrofuran and ether analogously to Example 3. Yield: 66.2% of theory, Melting point: 239-241’C Calc, (x H2O): C 64.48 H 7.44 N 5.37 Cl 13.91 Found: 64.30. 7.34 5.52 13.69 Example 14 2-f(N-(2-(Methyl-naphth-l-yl)-methyl)-hexahvdroazepin-3-yl)-methyl 1 -6.7-dimethoxv-l.2.3,4-tetrafavdroisp.quinpline-hydrochloride Prepared from 2-[(N-(2-(methyl- naphth-l-yl)-methyl)hexahydro-azepin-3-yl)-methyl]-6,7-dimethoxy-1-oxo1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran and ether analogously to Example 3.
Yield: 73.8% of theory, Melting point: 182-184"C Calc, (x H2O): C 65.56 H 7.70 N 5.09 Cl 12.90 Found: 65.52 7.57 5.32' 12.72.
Example 15 2=118.- (4- (Naphthyl-2-oxy)_ butyl l_=pyrrplid-3-yl) methyl!-6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdroigpquinoline-hydrpchlQEide Prepared from 2-(pyrrolid-3-yl-methyl)-6,7-dimethyll-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(4bromo-butyloxy)-naphthalene analogously to Example l. Yield: 30% of theory.
Melting point: 133-136eC Calculated: C 67.02 H 6.92 N 5.21 Br 14.86 Found: 67.26 7.03 5.36 14.89 Example 16 Z--.r_iN-i2-Methyl-naphth-l-yl) -methyl) -pyrrol id-3-yl) methyl! -6.7-dimethyl-1-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2-(pyrrolid-3-yl-methyl)-6,7-dimethyl1- oxo-isoquinoline and 1-chloromethyl-2-methylnaphthalene analogously to Exanple 1.
Yield: 32.5% of theory, Melting point: 142-144’C Calculated: C 69.34 H 7.69 N 5.77 Br 7.37 Found: 69.59 7.63 5.72 7.89 Exanple 17 2- f (N- (2- (5-Methyl-6-methoxy-naphth-2-yl) -ethvl)pyrrolid-3-yl) -methyll -6.7-dimethyl-1-oxo-l, 2 ..3,.4tetrahydro-isoauinoline-hydrobromide Prepared from 2- [N- (pyrrolid-3-yl-methyl) ] -6,7-dimethyl1- oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Exanple 1.
Yield: 19% of theory.
Melting point: 230-232°C Calculated: C 67.02 H 6.93 N 5.21 Br 14.86 Found: 67.10 7.12 5.33 15.01 Example 18 2- r (N- (2- (Naphth-2-yll -ethvl) -pyrrolid-3-vl) -methyll 6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahydro-isoquinoline= hydrochloride Prepared from 2 - (pyrrolid-3 -yl -methyl )-6,7-dimethoxy1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2bromoethyl)-naphthalene analogously to Exanple 1.
Yield: 7.8% of theory, Melting point: 219-221C calc. (X H20) : C 67.39 H 7.07 N 5.61 Cl 7.10 Found: 67.21 7.23 5.57 7.63 Example,-19 2-Γ (N-(2-(6-Methoxy-naphth-2-vl)-ethvl)-pyrrolid-3-vl) methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdro10 isoquinoline-hydrochloride Prepared from 2- (pyrrolid-3-yl) -methyl) -6,7-dimethoxy1- oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2bromoethyl)-6-methoxy-naphthalene analogously to Exanple 1.
Yield: 39.2% of theory.
Melting point: 224-226"C Calc, (x H20) : C 65.84 H 7.05 N 5.29 Cl 7.05 Found: 66.08 7.13 5.39 6.77 Example_2£L 2- f (Naphth-2-yl) -propyl) -piperid-3-yl) -methyl! 6 ..7-dimethyl-l-QXQ-l. 2.3«J-,tetrahydro-isoquinol insx hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-chloromethyl-N-[3-(naphth-2-yl) propyl]-piperidine analogously to Example 2.
Yield: 40.4% of theory, Melting point: 185-187eC Calculated: C 75.52 H 7.82 N 5.87 Cl 7.43 Found: 75.39 7.85 5.82 7.52 Example 21 2- f (Ν- (3- (Naphthyl-2-oxy) -propyl) -piperid-2-yl) ethvl 1 -6.7-methvlenedioxv-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2-(piperid-2-yl) -ethyl-6,7-methylenedioxy1- oxo-isoquinoline and 2-(3-chloropropoxy)-naphthalene analogously to Exanple 1.
Yield: 21.2% of theory.
Melting point: 85-87"C Calc, (x H2O): C 66.59 H 6.89 N 5.17 Cl 6.53 Found: 66.77 6.98 4.95 6.74 Example 22 2- Γ(N-(3-(Naphthyl-2-oxy)-propyl)-piperid-3-yl) methyll -6.7-dimethyl-l. 2.3.4-tetrahydro-isoqpinol inedihydrpchloride Prepared from 2-[(N-(3-(naphthyl-2-oxy)-propyl)piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 53% of theory, Melting point: 133-135"C Calc, (x H2O): C 68.30 H 6.87 N 5.31 Cl 13.44 Found: 68.05 6.85 5.23 13.03 Ba£amplfiJ2l - Γ (N- (3 - (Naphthyl-2-oxv) -oronvl) -piperid-3-yl) methyl]-6. Jz.methylenediPxyzl^j.Jj.J-tetrahydroispquinoline-dihydrpchlpride ♦ Prepared from 2-[(N-(3-(naphthyl-2-oxy)-propyl)piperid-3-yl) -methyl] -6,7-meth.ylenedioxy-l-oxo-l, 2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in - 67 tetrahydrofuran/ether analogously to Example 3.
Yield: 44.7% of theory, Melting point: 130-132’C Calc, (x H20): C 63.62 H 6.62 N 5.11 Cl 12.95 Found: 63.49 6.86 4.97 12.64 Example 24 2- Γ (N- ((2-Methyl-naphth-1-yl) -methyl) -piperid-3-vl) 10 methyl)-6.7-dimethoxy-l.2.3.4-tetrahydro-isoquinolinedihydrochloride Prepared from 2-[(N-((2-methyl-naphth-1-yl)-methyl)piperid-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,415 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 80.5% of theory.
Melting point: 210-212’C Calc. (X H20): C 65.05 H 7.53 N 5.23 Found: 65.23 7.78 5.03 Example 25 2- Γ2- (N- (2- (6-Methoxy-naphth-2-yl) -ethyl) -piperid-2-yl) 25 ethyl) -6.7-methylenedioxy-l-oxo-l. 2.3.4-tetrahydroAsoquinpline-hydrochloride Prepared from 2-(2-(piperid-2-yl)-ethyl]-6,7-methylenedioxy-l-oxo-1,23,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-6-methoxy-naphthalene analogously to Exanple 1.
Yield: 27.6% of theory, Melting point: 112-117’C Calc, (x H2O): C 67.74 H 6.82 N 5.26 Found: 67.54 6.73 5.47 Cl 6.65 6.86 Example 26. - Γ (Ν- (2 - (6-Naphth-1-yl) -ethyl) -piper id-3-vll -methyl! 6.7- dimethoxy-l-oxo-l. 2.3.4 -tetrahydro-isoauinolinehydppphlpride Prepared from 2-[ (piperid-3-yl)-methyl]-6,7-dimethoxy1- oxo-l ,2,3,4-tetrahydro-isoquinoline and 1-(2-benzenesulphonyl oxy- ethyl) -naphthalene analogously to Example 1.
Yield: 26.9% of theory, Melting point: 220-225’C Calculated: C 67.89 H 7.27 N 5.46 Cl 6.91 Pound: 67.75 . 6.92 5.56' 7.00 Example 27 2- f (N- (2- (Naphth-2-yl) -ethvl)-piperid-3-vl)-methvll 6.7- methylenedioxy-l-oxo-l.2.3. 4-_tetrahvdro= isoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7methylenedioxy-l-oxo-l ,2,3,4-tetrahydro-isoquinoline and 2- (2-benzene-sulphonyloxy-ethyl) -naphthalene analogously to Example 1.
Yield: 27.9% of theory, Melting point: 128-130*C Calc, (x H2O) : C 67.66 H 6.69 N 5.63 Cl 7.13 Pound: 67.64 6.70 5.76- 7.35 Example .28 2- Γ (N- (2- (5-Methyl-6-methoxy-naphth-2-yl) -ethyl) piperid-3-yl) -methvll -6.7-methylenedioxy-l-oxo-l. 2.3.4tetrahydro- i soquinol ine-hydrochloride Prepared from 2-[ (piperid-3-yl)-methyl]-6,7methylenedioxy-l-oxo-l, 2 , 3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Yield: 51.2% of theory, Melting point: 128-131*C Calculated: C 68.88 H 6.74 N 5.34 Cl 6.77 Found: 68.90 6.61 5.30 7.05 Example,, 2.9. 2- Γ (N- ( (2-Methyl-naphth-l-vl) -methyl) -piperid-3-vl) methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloromethyl-2-methyl-naphthalene analogously to Example 1.
Yield: 57.9% of theory, Melting point: 212-214"C Calc, (x 2 H2O):C 67.63 H 7.63 N 5.44 Cl 6.88 Found: 67.46 7.56 5.54 6.67 Example.., 2- r (N- (4- (Naphthyl-2-oxy) -butyl) -piperid-3-vl) -methvl 1 6.7-dimethoxy-l-Qxo-l .,2.3.4,7.tetrahydrQ-isoaainQlinehydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(4bromo-butoxy)-naphthalene analogously to Example 1. Yield: 46.3% Of theory.
Melting point: 80-84°C Calc, (x H2O) : C 66.83 H 7.41 N 5.03* Cl 6.36 Found: 66.79 7.22 4.90 6.64 Example 31 2-Γ(N-(2- (6-Methnxv-naphth-2-yl) -ethyl) -ninerid-3-yl) methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroifiQguino.line-hydrQ.chl oxide Prepared from 2-( (piperid-3-yl) -methyl] -6,7-dimethoxy1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2bromo-ethyl) -6-methoxy-naphthalene analogously to Example 1.
Yield: 22.8% of theory, Melting point: 80-85"C Calc.: (χ H2O x HC1 x CH3COCH3): C 64.01 H 7.65 N 4.52 Cl 5.72 Found: 64.26 7.70 4.62 5.49 Example. 32 2-Γ3-(N- (2-(6-Methoxy-naphth-2-yl)-ethyl)-piperid-3-yl)propyl!-6.7-methylenedioxy-1-oxo-l.2.3.4-tetrahvdroisocruinoline Prepared from 2- [N-(3-(piperid-3-yl)-propyl]-6,7methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl) -6-methoxy-naphthalene analogously to Exanple 1.
Yield: 36.8% of theory, Melting point: 118-121°C Calculated: C 74.37 H 7.25 N 5.60 Found: 74.60 7.43 5.65 Example 33 2- Γ3- (N- (2- (Naphth-l-yl) -ethyl) -piperid-3-yl) -propvll 61,7rinethylenediQxy-l-Qxo-l. 2.3.4-tfitxahydxoifipquinol ine-hydroshloride Prepared from 2- [N- (3-(piperid-3-yl)-propyl]-6,7methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and - 71 1-(2 benzenesulphonyloxy-ethyl)-naphthalene analogously to Example 1.
Yield: 20.8% of theory, Melting point: 195-197"C Calculated: C 71.07 H 6.95 N 5.53 Cl 6.99 Found: 71.30 6.95 5.65 6.80 Example 34 2-Γ2-(N- (2-(5-Methyl-6-methoxy-naphth-2-yl)-ethyl)piperid-2-yl)-ethyl!-67-dimethoxy-1-oxo-l.2.3.4tetrahydro-isoquinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl.) -ethyl] -6,7-dime thoxy15 l-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl) -5 -me thyl -6 -me thoxy- naphthalene analogously to Example l.
Yield: 33.6% of theory, Melting point: 95-100"C Calc, (x H2O) : C 68.38 H 7.52 N 4.98 Cl 6.30 Found: 68.14 7.43 4.92 6.77 Example 35 2- ί (N- (3--iNaBhthyJ.-2-,Qay).-prQpyl) -piperid-3-zyl)— methyll-6.7-dimethylenedioxy-l-oxo-l.2.3.4-tetrahvdroisocruinol ine-hydrochloride Prepared from 6,7-methylenedioxy-1-oxo-l,2,3,430 tetrahydro-isoquinoline and 3-chloromethyl-N-[3(naphthyl-2-oxy)-propyl]-piperidine analogously to Example 2.
Yield: 27.3% of theory.
Melting point: 104-106*C Calc, (x H2O) : C 66.09 H 6.69 N 5.31 Cl 6.72 found: 66.19 6.34 5.24 7.22 Example 36 2- ί (N- (3= iMaphthyl-2-*.Pxy)-zprppyli .-piperidzS^yl) methyl] £. 7-dimethPxy.rlr.oxo-l.« 2,3.. 4-tetrahydroi spquinoline -rhydrachlor ide Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-chloromethyl-N-[3-(naphthyl 2-oxy)-propyl]-piperidine analogously to Example 2. Yield: 28.6% of theory, Melting point: 191-193’C Calc, (x H2O): C 66.34 H 7.23 N 5.15 Cl 6.53 Found: 66.59 7.19 5.03 6.65 Example 37 2-Γ(N-(3-(Naphthyl-2-oxy)-propyl)-hexahydro-azepin-3yl)-methyl1-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2- [(hexahydro-azepin-3-yl)-methyl]6,7-dimethoxy-l-oxo-isoquinoline and 2-(3chloropropoxy)-naphthalene analogously to Exanple 1. Yield: 16.1% of theory.
Melting point: 86-88"C Calc, (x H2O) : C 66.83 H 7.42 N 5.03 Cl 6.36 Found: 66.90 7.40 5.26 6.87 Example 38 2- Γ(N- (3- (Naphthyl-2-oxy) -propyl) -hexahydro-azepin3- yl) -methyl 1 -6.7-dimethyl-1-oxo-l. 2.3.4-tetrahydroisoguinoline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-chloromethyl-N-[3-(naphthyl2-oxy) -propyl] -hexahydro-azepine analogously to Exanple 2.
Yield: 22.5% of theory, Melting point: 191-193’C Calculated: C 73.42 H 7.75 N 5.52 Cl 6.99 Found: 73.37 7.67 5.52 7.12 Example ,39 2-Γ(N-(2-(5-Methyl-6-methoxv-naphth-2-yl)-ethvl)hexahyflro-azepin-3-.yl ^methyll -6.7-dimethQxy-lrQXP1.2.3.4- tetrahydro-isoouinoline-dihydrochloride Prepared from 2-[(N-(2-(5-methyl-6-methoxy-naphth-2-yl)ethyl) -hexahydro-azepin-3-yl) -methyl] -6,7-dimethoxy1- oxo-l ,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 77.6% of theory, Melting point: 170-172’C Calc. (X H2O): C 64.96 H 7.49 N 4.73 Cl 11.98 Found: 65.11 7.62 4.95 11.84 Example 40 2- ί (N- (2- (5-Methyl-jS-methoxy-naphth-2-yl) -ethyl) hexahydro-azepin-3-yl) -methyl! -6.7-dimethoxv-l-oxo1.2.3.4- tetrahydro-isoquinoline Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2-bromoethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Yield: 43.5% of theory, Melting point: 125-127’C Calculated: C 74.39 H 7.80 N 5.42 Found: 74.31 7.82 5.35 - 74 Example 41 - f (Ν- (2-Methyl-naphth-1-yl) -methyl) -hexahydro-azepin3-yl) -methyl! -6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahvdroisoquinoline-hvdrochloride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl] 6.7- dimethoxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 1- chloromethyl-2-methyl-naphthalene analogously to Example 1.
Yield: 67.5% of theory, Melting point: 128-130’C Calc, (x 2 H2O): C 66.10 H 7.58 N 5.13 Cl 6.50 Found: 66.24 7.44 5.23 6.85 Example42 2- Γ (N- (4- (Naphthyl-2-oxv) -butyl) -hexahvdro-azepin-3-νΙΠ methyl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl] 6,7 -dimethoxy-1 -oxo-1,2,3,4-tetrahydro-isoquinoline and 2- (4-bromo-butyloxy) -naphthalene analogously to Example 1.
Yield: 26% of theory, Melting point: 192-194"C Calculated: C 69.22 H 7.80 N 5.04 Cl 6.38 Found: 70.01 7.70 5.15 6.48 Example 43 2- Γ (N- (2- (Naphth-l-yl) -ethyl) -hexahydro-azepin-3-vl) methyl! -6.7-methylenedioxy-l-oxo-l. 2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] 6.7- methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2- (2-benzenesulphonyloxy-ethyl) -naphthalene analogously to Exanple 1.
Yield: 15.4% of theory, Melting oint: 236-238"C Calc, (x H20): C 69.40 H 6.82 N 5.58 Cl 7.06 Found: 69.07 6.74 6.13 7.29 Example,44 2- f (N- (2- (Naphth-2-yl) -ethyl) -hexahydro-azepin-3-vl) methyll -6.7-methylenedioxyjJL-QXQ-l, 2.3.4-tetrahydrpisoguinpline-hydrobiOmide Prepared from 2-[ (hexahydro-azepin-3-yl)-methyl]15 6,7-methylenedioxy-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-naphthalene analogously to Exanple 1.
Melting point: 100-102"C Yield: 31.6% of theory, Calculated: C 64.80 H 6.18 N 5.21 Br 14.86 Found: 65.02 6.07 5.39 14.78 Example 45 2 - Γ (N- (2 - (6-Methoxy-naphth-2-yl) -ethyl) -hexahvdroazepin-J-yl) -methyl! 7-methylenediPxy-l-oxP7lJ2^3.4tetrahydrp- ispquinpl ine-hydrpchlpride Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] 30 6,7-methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 2- (2-bromo-ethyl) -6-methoxy-naphthalene analogously to Exanple 1.
Yield: 34.1% of theory.
Melting point: 147.-149*C Calc, (x H20) : C 68.62 H 7.10 N 5.33 Cl 6.75 Found: 68.88 6.98 5.41 6.78 Example 2-ί(N-(2-(5-Methyl-6-methoxy-naphth-2-yl)-ethyl)hexahydro-azepin-3-yl) -methyl! -6.7-methylenedioxy5 1-qxq-I,2,3.4-tetrahydro-isoduinoline-hydrochloride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]6,7-methylenedioxy-l-oxo-isoquinoline and 2-(2bromo-ethyl)-5-methyl-6-methoxy-naphthalene analogously to Example 1.
Yield: 36.1% of theory, Melting point: 112-114’C Calc, (x H2O): C 67.07 H 7.08 N 5.04 Cl 6.38 Found: 67.13 7.15 4.97 6.56 Example 42 - KN-.( 3 -JL4 -Methoxy-phenoxy) --propylL-piperid- 3-yl) methyl!-6.7-dimethoxy-1.2.3.4-tetrahydro-isoquinoline20 dihydrachloride Prepared from 2-[(N-(3-(4-methoxy-phenoxy)-propyl)piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 88.5% of theory, Melting point: 189-191’C Calculated: C 59.44 H 7.76 N 5.13 Cl 12.99 Found: 59.55 7.99 5.12 12.61 Example 48 2- f (N- (2- (3.4-Dimethoxy-phenyl) -ethyl) -piperid-3-yl) methyl!-6.7-dimethoxy-1.2.3.4-tetrahydro-iBoquinoline35 dihydrochloride Prepared from 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,477 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 92.8% of theory.
Melting point: 175-176’C Calculated: C 60.66 H 7.35 N 5.33 Cl 13.49 Pound: 60.58 7.56 5.32 13.22 Example 49 3- r (N- (3- (Indolyl-3) -propyl) -pyrrolidyl-3) -methvl 1 7.8-methylenedioxy-1.3.4.5-tetrahydro-2H-3-benzazepinedihydrochloride ,...=. JL.5 x hydrate Prepared from 7,8 -methylenedioxy-1,3,4,5- tetrahydro- 2H15 3-benzazepine and 3-(benzene-sulphonyloxymethyl)-N-[3indolyl-3)-propyl]-pyrrolidine analogously to Exanple 2. Yield: 75% of theory.
Melting point: 191-193"C Calculated: C 61.01 H 7.21 N 7.90 Cl 13.34 Found: 60.90 7.27 7.85 13.70 Example 50 2-Γ (N- (3- (3-Methoxy-phenoxy) -propyl) -piperid-3-vl) 25 methyll -6.7-methylenedioxy-1.2.3,4-tetrahydro^ isoquinoline-dihydrochloride Prepared from 2- [ (N- (3- (3-methoxy-phenoxy) -propyl) piperid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,430 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 94.5% of theory, Melting point: 169-171’C Calculated: C 57.03 H 7.36 N 5.11 Cl 13.86 Found: 56.91 7.26 5.15 13.68 Example 51 2- ί (Ν- (2- (3.4-Dimethoxy-phenvl) -ethyl) -piperid-3-vl) methyll -6.7-dimethvl-l. 2.3.4-tetrahydro-isoquinolinedihydrochloride Prepared from 2- [ (N- (2- (3,4-dimethoxy-phenyl) -ethyl) piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinol ine and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 91.3% of theory.
Melting point: 140-142’C Calculated: C 62.00 H 8.34 N 5.27 Cl 13.44 Found: 61.85 8.27 5.31 13.33 Example ,52 - f (N- (3- (4-Methoxy-phenoxy) -propyl) -piperid-3-vl) methyl! -6.7-dimethyl-1.2.3.4-tetrahydro-isoquinolinedihydrochloride Prepared from 2 - [ (N- (3- (4-methoxy-phenoxy) -propyl) piperid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 88.3% of theory.
Melting point: 170-172’C Calculated: C 63.14 H 8.24 N 5.65 Cl 14.31 Found: 63.09 8.33 5.82 14.02 Example 53 2- Γ (N- 12-(3.4-Dimethoxy-phenyl) -ethyl) -piperid-3-yl) methyll-6.7-methylenedioxy-1.2.3.4-tetrahydroisocruinoline-dihydrochloride Prepared from 2-[ (N-(3-(3,4-dimethoxy-phenyl)-ethyl)piperid-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,479 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 93.3% of theory, Melting point: 150-154"C Calculated: C 60.01 H 7.34 N 5.39. Cl 13.64 Found: 59.96 7.41 5.25 13.43 Example 54 2-Γ(N-(3-(4-Methoxy-phenoxy)-propyl)-piperid-3-vl)methyl!-6.7-methylenedioxy-1.2.3.4-tetrahydroi soquinol ine - dihydrochl or ide Prepared from 2-[ (N-(3-(4-methoxy-phenoxy)-propyl) piperid-3-yl-3) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 95.3% of theory.
Melting point: 182-185"C Calculated: C 61.05 H 7.09 N 5.48 Cl 13.86 Found: 61.10 6.95 5.68 13.55 Example 55 2- Γ2-(N-(3-(3.4-Methylenedioxy-phenoxy)-propyl)plBexid=3.-:yJL).,-.fithyll -6.7-dimethoxy-l-oxQ-l .2,3,4fcet.rahydrQz.isfiguinQl,insdtiydrQchlQride Prepared from 2- [ (piperid-3-yl) -ethyl] -6,7-dimethoxy1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro3- (3,6-methylenedioxy-phenoxy)-propane analogously to Exanple 1.
Yield: 35.5% of theory, Melting point: 97-100*C Calculated: C 59.09 H 7.28 N 4.62 Cl 6.65 Found: 58.97 7.36 4.66* 6.52 Example 56 2-Γ2 - (Ν-(2-(3. 4-Dimethoxy-phenyl)-ethvl)-piperid-3-yl)ethvl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoauinoline-hydrochloride Prepared from 2-((piperid-3-yl)-ethyl]-6,7-dimethoxy1- oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 1-bromo2- (3,4-dimethoxy-phenyl)-ethane analogously to Example 1.
Yield: 35.9% of theory, Melting point: 103-105eC Calculated: C 62.60 H 7.79 N 5.21 Cl 6.83 Found: 62.41 7.82 5.09 7.19 Example 57. 2- Γ3- (N- (2-(3.4-Dimethoxy-phenyl) -ethvl) -pjperid-3-vl) propyll -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2-(3- (piperid-3-yl) -propyl] -6,7-dimethoxy1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo2- (3,4-dimethoxy-phenyl)-ethane analogously to Example 1.
Yield: 32.6% of theory.
Melting point: 102-106*C Calculated: C 63.20 H 7.86 N 5.08 Cl 6.43 Found: 63.39 7.90 4.86 6.13 Example 58 2- Γ3- (N- (3- (3.4-Methylenedioxv-phenoxy) -nropyl) piperid-3-vl) -propyll -6.7-dimethoxy-1-oxo-1.2.3.4tetrahydro-isoquinoline-hydrochloride Prepared from 2-(3- (piperid-3-yl) -propyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro81 3-(3,4-methylenedioxy-phenoxy)-propane analogously to Exanple 1.
Yield: 29.7% of theory, Melting point: 97-100’C 5 Calculated: C 61.63 H 7.31 N 4.96 Cl 6.47 Found: 61.94 7.46 5.16 6.48 Example 5.2. 2 - Γ (N- (3.4-Dimethoxy-benzvl) -piperid-3-yl) -methyl! 6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydro-isoquinolinehydrQchlorj.de Prepared from 2-(piperid-3-yl-methyl)-6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 3,4-dimethoxy benzylbromide analogously to Example 1.
Yield: 53.3% of theory.
Melting point : 127-132’C Calculated: C 63.58 H 7.18 N 5.70 Cl 7.22 Found: 63.30 7.22 5.52 7.14 Example 6Q. 2 - r (N- (3 - (4-Methoxy-phenyl) -propyl) -piperid-3-vl)methyll -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydroi soquinoline-hydrochloride Prepared from 2 - (piperid- 3 -yl -methyl )-6,7 -dimethoxy3Q 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-bromo3-(4-methoxyphenyl)-propane analogously to Exanple l. Yield: 42% of theory, Melting point: 229-231°C Calculated: C 66.31 H 7.63 N 5.73 Cl 7.25 Found: 66.27 7.64 5.65 7.33 Example .61 2- Γ2-(Ν-(3-(3-Methyl-phenoxy)-propyl)-pjperid-2-vl)ethvl 1 -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisQquin,Qline-hydrQchlpride Prepared from 2-(2-(piperid-2-yl)-ethyl]-6,7-dimethoxy1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3- (3-methyl-phenoxy) -propane analogously to Example 1. Yield: 52.4% of theory, Melting point: 142-144eC Calculated: C 66.85 H 7.81 N 5.57 Cl 7.05 Found: 66.73 7.68 5.53 6.94 Example 62 2- Γ2-(N- 12-(3,4-Dimethoxy-phenyl)-ethvl)-piperid-2-yl)ethvll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo2- (3,4-diraethoxy-phenyl)-ethane analogously to Exanple 1.
Yield: 47.3% of theory.
Melting point: 150-155eC Calculated: C 64.72 H 7.68 N 5.39 Cl 6.82 Found: 64.40 7.83 5.27 6.90 Example 63 2- Γ2-(N-(3-Benzyloxy-propyl)-piperid-2-yl)-ethyl!6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahydro-isogruinolinefaydEPchlpride Prepared from 2- [2- (piperid-2-yl) -ethyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3- benzyloxy-propane analogously to Exanple 1.
Yield: 56.3% of theory, Melting point: 116-120eC Calculated: C 66.85 H 7.81 N 5.57 Cl 7.05 Found: 66.60 7.75 5.25 7.25 Example 64 2- Γ2- (N- (4-(4-Methoxy-phenyl)-butyl)-piperid-2-vl) ethyl!-6.7-dimethoxy-1-oxo-1.2.3.4-tetrahvdrOisoguinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-bromo4-(4-methoxy-phenyl)-butane analogously to Exanple l. Yield: 42.8% of theory, Melting point: 107-112’C Calculated: C 67.36 H 7.99 N 5.42 Cl 6.86 Found: 67.16 8.05 5.35 7.34 Example - J2 - (N- (3-(3. S.zDimethoxyzpbenQxylzprppyl) 2- yl)-ethyl!-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2- [2- (piperid-2-yl) -ethyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3- (3,5-dimethoxy-phenoxy)-propane analogously to Exanple 1.
Yield: 56.3% of theory, Melting point: 127-132eC Calculated: C 61.41 H 7.64 N 5.10 Cl 6.46 Found: 61.56 7.65 5.28 6.89 Example.. 66. 2- Γ2- (N- (3- (3 .4-Methyleneriioxy-phenoxv)-propyl)piperid-2-yl)-ethyl1-6.7-dimethoxv-l-oxo-l,2.3,4tetrahydro-isoquinoline-hydrochloride Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxyl-oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 1-chloro3- (3,4-methylenedioxy-phenoxy)-propane analogously to Exanple 1.
Yield: 49% of theory.
Melting point: 118-120C Calculated: C 63.09 H 7.00 N 5.26 Cl 6.65 Found: 62.90 7.04 5.46* 6.79 Example ,62 - UN- (3 - (3.5-Dimethoxy-phenoxy) -propyl·) -piperid-3-vl) methyll -6.7-dimethoxv-l-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2 - [ (piperid-3 -yl) -methyl] - 6,7 -dimethoxy1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1-chloro3- (3,5-dimethoxy-phenoxy) -propane analogously to Exanple 1.
Yield: 37.5% of theory, Melting point: 98-102’C Calculated: C 62.85 H 7.35 N 5.24 Cl 6.63 Found: 62.81 7.41 5.10' 6.75 Exanple 68 - Γ (N- (3- (3.4-Methylenedioxy-phenoxy) -propyl) -piperid3-yll -methyl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydroisoquinoline-hvdrochl or ide Prepared from 2- [ (piperid-2-yl) -methyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3-(3,4-methylenedioxy-phenyl)-propane analogously to Example 1.
Yield: 50% of theory, Melting point: 236-238’C Calculated: C 64.46 H 7.01 N 5.57 Cl 7.04 Pound: 64.30 6.97 5.59 7.08 Example -69 - f (N- (3- (3.4-Methvlenedioxv-phenoxv) -propyl) -pjperid3-yl) -methyl! -6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2- [ (piperid-2-yl) -methyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and l-chloro3-(3,4-methylenedioxy-phenoxy)-propane analogously to Example 1.
Yield: 46.2% of theory, Melting point: 149-153’C Calculated: C 60.38 H 6.94 N 5.21 Cl 6.60 Found: 60.30 6.93 5.29 6.37 Example 70 - Γ (N- (3- (2.6-Dimethyl-phenoxy) -propyl) -pjperid3-yl) -methyl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroi soquinoline-hydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3-(2,6-dimethyl-phenoxy)-propane analogously to Exanple 1.
Yield: 53.3% of theory.
Melting point: 131-135’C Calculated: C 66.85 H 7.81 N 5.57 Cl 7.05 Found: 66.88 7.95 5.59 6.85 Example 71 2- Γ(N-(4-(2.4-Diehloro-phenoxy)-butyl)-piperid3- yl)-methvll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethoxy1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro4- (2,4-dichloro-phenoxy)-butane analogously to Example 1.
Yield: 54.1% of theory.
Melting point: 125-128’C Calculated: C 58.12 H 6.32 N 5.02 Cl 19.06 Found: 58.21 6.38 5.08 18.85 Example 72 2- ί(N- (2-(3.4-Dimethoxy-phenyl)-ethyl)-pioerid3- yl) -methyl 1 -6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2- I (piperid-3-yl) -methyl] -6,7-dimethoxy1- oxo-l, 2,3,4-tietrahydro-isoquinoline and 1-bromo- * 2- (3,4-dimethoxy-phenyl)-ethane analogously to Exanple 1.
Yield: 57.5% of theory, Melting point: 118-121‘C Calculated: C 64.21 H 7.38 N 5.55 Found: 64.18 7.36 5.19 Exanple 73 2- Γ (N- (3-(3.4-Dimethoxy-phenoxv) -propyl) -piperid3- yl) -methyll -6.7-dimethoxy-l-oxo-l .2,3.4-tetrahydroisoauinoline-hydrochloride Prepared from 2-[ (piperid-3-yl)-methyl]-6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3-(3,4-dimethoxy-phenoxy)-propane analogously to Exanple 1.
Yield: 62.5% of theory, Melting point: 112-115eC Calculated: C 60.80 H 7.47 N 5.24 Found: 60.65 7.69 5.27 Example -Z4 - Γ (N- (3 - (3.4-Dimethoxy-phenoxy) -propvl) -piperidyl-3) methyll -6.7-methylenedioxy-1-oxo-1.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 2 - [ (piperid-3-yl)-methyl]-6,7methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 1 - chloro- 3 -(3,4 -dimethoxy-phenoxy) -propane analogously to Exanple 1.
Yield: 60% of theory, Melting point: 97-100’C Calculated: C 60.38 H 6.94 N 5.40 Cl 6^60 Found: 60.20 6.97 5.21 6.83 Example 75 2-Γ(N- (2- (4-Methoxy-phenyl) -ethyl) -piperid-3-vl) methyll -6.7-methylenedioxy-1-oxo-l. 2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2-[ (piperid-3-yl)-methyl]-6,7methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and l-chloro-2-(4-methoxy-phenyl) -ethane analogously to Exanple 1.
Yield: 71.4% of theory.
Melting point: 195-197"C Calculated: C 62.94 H 6.97 N 5.87 Cl 7.73 Found: 62.90 6.98 5.68 8.04 Example 76 2- Γ(N-(2-(3.4-Dimethoxy-Phenyl)-ethyl)-biberid3- vl)-methyl!-6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdroisoqruinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethyl1- oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 1-bromo2- (3,4-dimethoxy-phenyl)-ethane analogously to Exanple 1.
Yield: 41.9% of theory, Melting point: 132-134’C Calculated: C 63.57 H 8.10 N 5.49 Cl 6.95 Found: 63.70 8.26 5.45 7.13 Example-77 2- Γ(N-(3-(4-Methoxy-phenoxy)-propyl)-piperid-3yl)-methyll-6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdroisQguinQl ine,? hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7-dimethyll-oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 1-chloro3- (4-methoxy-phenoxy)-propane analogously to Exanple 1. Yield: 57.8% of theory, Melting point: 144-146°C Calculated: C 68.55 H 7.88 N 5.92 Cl 7.49 Found: 68.45 7.80 6.11 7.33 Bxample-78 2.--LCN- (3- (3-MethQxy-phenQxy}-prQpyll-piperiflr3-. vl.) -methyll -6.7-methylenedioxy-1-oxo-1.2.3.4-tetrahvdroisoguinoline-hyflrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7methylenedioxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3- (3-methoxy-phenoxy) rpropane analogously to Example l.
Yield: 32.5% of theory, Melting point: 142-145’C Calculated: C 60.58 H 6.95 N 5.52 Cl 6.99 Found: 60.42 6.92 5.50 7.18 Example 79 2- f(N-(3-(3-Methyl-phenoxy)-propyl)-pineridr3-yl) methyl!-6.7-methylenedioxy-l-oxo-l.2.3.4-tetrahydroisoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-6,7methylenedioxy-l-oxo-l, 2,3,4-tetrahydro-isoquinoline and 3- (3-methyl-phenoxy) -1-chloro-propane analogously to Example 1.
Yield: 31.6% of theory, Melting point: 178-180’C Calculated: C 63.59 H 6.97 N 5.70 Cl 7.22 Found: 63.59 6.92 5.86 7.50 Example so 2- f (N- (3- (4-Methoxy-N-methyl-phenylamino) -propvl) piperid-3-yl)-methyl!-6.7-dimethoxy-l-oxo-l.2.3.4tetrahydro-isoguinoline-dihydrochloride Prepared from 2 - [ (piperid-3-yl) -methyl] -6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 1-chloro3- (4-methoxy-N-methyl-phenylamino) -propane analogously to Example l.
Yield: 52.5% of theory.
Melting point: 180-183’C Calculated: C 60.64 H 7.45 N 7.58 Cl 12.79 Found: 60.50 7.35 7.56 12.87 Example 81 2- Γ(N- (3-(4-Methoxy-phenoxy)-propyl)-pvrrolidvl3)-methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and N-(3-(4-methoxy-phenoxy)-propyl)3- benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 84.4% of theory, Melting point: 142-144°C Calculated: C 63.60 H 7.18 N 5.71 Cl 7.22 Found: 63.75 7.12 5.64 7.32 Example 82 2- Γ (N-(3- (6-Methoxy-naphthyl-2-.oxy) -propvD -Pvrrolid3- yl)-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdrQisoquinoline Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl)N- (6-methoxy-naphthyl-2-oxy) -pyrrolidine analogously to Example 2.
Yield: 47% of theory.
Melting point: 142-144’C Calculated: C 71.41 H 7.19 N 5.55 Found: 71.14 7.16 5.53 2- Γ (N-.(3- (4-Methoxy-phenoxy) -propyl) -pyrrolid-3vl) -methyl! -6.7-dimethoxv-l. 2.3.4-tetrahvdroisoquinol ine-dihydrochloride Prepared from 2-[ (N-(3-(4-methoxy-phenoxy)-propyl) pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,491 tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 90.9% of theory, Melting point: 248-250*C Calculated: C 60.81 H 7.46 N 5.46 Cl 13.81 Found: 60.79 7.61 5.48 13.84 Example..J.4 2 - r (N- (3 - (4-Methoxv-Phenoxy) -propyl) -Pvrrolid-3yl)-methyll-6.7-dimethyl-l-oxo-l.2.3.4-tetrahydroisoquinoline -hydrochloride Prepared from 6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydro15 isoquinoline and N- [3-(4-methoxy-phenoxy) -propyl] 3-benzenesulphonyloxymethyl-pyrrolidine analogously to Exanple 2.
Yield: 60.6% of theory, Melting point: 118-121"C Calculated: C 68.03 H 7.69 N 6.10 Cl 7.72 Found: 67.90 7.71 6.04 7.90 Example. ,85 2-Γ(N-(2- (3.4-Dimethoxy-phenyl) -ethyl) - pyrrol id 3-yl) -methyll -6.7-dimethoxy-1-oxo-1.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro30 isoquinoline and N- [2- (3,4-dimethoxy-phenoxy) -ethyl] 3-benzenesulphonyloxymethyl-pyrrolidine analogously to Exanple 2.
Yield: 56.7% of theory, Melting point: 116-118C Calculated: C 63.60 H 7.19 N 5.71 Cl 7.22 Found: 63.82 7.32 5.60 7.66 Example 86 2- Γ (Ν- (3- (4-Methoxy-phenoxy) -propvl) -pvrrolid-3yl) -methyll -6.7-dimethyl-l. 2.3.4-tetrahvdroisoquinoline-dihydrochloride Prepared from 2-[N-(3-(4-methoxy-phenoxy)-propyl)pyrrolid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4tet rahydro -isoquinol ine and lithium aluminium hydride in tetrahydrofuran analogously to Exanple 3.
Yield: 90.9% of theory, Melting point: 243-246’C Calculated: C 64.85 H 7.95 N 5.82 Cl 14.73 Found: 64.88 7.92 5.63 14.80 Example 87 2- ί(N-(2-(3.4-Dimethoxy-ohenvl)-ethvl)-pvrrolid3- vl) -methyll-6.7-dimethoxy-l.2.3.4-tetrahvdroisoquinoline-dihydrochloride Prepared from 2-[(N- (2-(3,4-dimethoxy-phenyl) -ethyl) pyrrolid-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l, 2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 92.9% of theory, Melting point: 240-242’C Calculated: C 60.81 H 7.46 N 5.46 Cl 13.81 Found: 60.64 7.61 5.31 13.50 Example 88 2- f (N- (3- (Pyrid-4-yl) -propyl) -pyrrolid-3-vl) -methyl! 5.6-ditnefchyl-l-oxo-l. 3^dihvdro-isoindoledihydrochloride- semihydrate Prepared from 2-[(N-(3-pyrid-4-yl)-propyl)-pyrrolid3- yl)-methyl]-5,6-dimethyl-phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 65% of theory, Melting point: 119-122°C Calculated: C 62.02 H 7.24 N 9.43 Cl 15.92 Found: 62.25 7.47 9.39 15.90 Example 89 - f3 - (N-- .(3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -propyl! 5.6- dimethoxy-1-oxo-l. 3-dihvdro-isQindoledihydrochlaride -monohydiats Prepared from 2-[3-(N-(3-(pyrid-3-yl)-propyl)-piperid3-yl) -propyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Exanple 4.
Yield: 72% of theory.
Melting point: 118-121eC Calculated: C 59.08 H 7.43 N 7.95 Cl 13.41 Found: 59.02 7.23 7.12 13.27 Exanple 90 » 2- Γ(N-(3- (Pyrid-3-yl) -propyl) -piperid-3-vl).-methvll-5.6- dimethoxy-l-oxo-l. 3 -dihvdro-isoindoledihydrochloride-monohydrate Prepared from 2-[(N-(3-(pyrid-3-yl)-propyl)-piperid3- yl)-methyl]-5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Exanple 4.
Yield: 42% of theory.
Melting point: 91-96"C Calculated: C 59.08 H 7.43 N 7.95 Cl 13.41 Found: 59.02 7.23 7.12 13.27 Example 91 2- ί (Ν- (2- (6.7-Dimethoxy-isoquinol-4-vl) -ethyl) piperid-3-yl) -methyl! -5.6-dimethoxy-l-oxo-l 3-dihvdrοι so indole Prepared from 2-[(N- (2-(6,7-dimethoxy-isoquinol4-yl) -ethyl) -piperid-3-yl) -methyl] -5,6-dimethoxyphthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 64% of theory, Melting point: 85-88’C Calculated: C 65.39 H 7.19 N 7.88 Found: 65.16 7.27 7.53 Example 92 2-Γ2-(N-(3-(Pyrid-4-yl)-propyl)-piperid-2-yl)-ethvl! 5.6- dimethyl-1-oxo-1.3-dihydro-isoindole Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2-yl)-ethyl]-5,6-dimethyl-phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 73% of theory, Melting point: 103-104"C Calculated: C 76.68 H 8.49 N 10.73 Found: 76.57 8.54 10.60 Example„.J3 2- Γ (N- (3- (Pyrid-4-yl) -propvl) -pvrrolid-3vl) -methyl! 5.6- dimethyl-l. 3 -dihydro-isoindole-trihydrochlorideaemihydrate Prepared from 2- [ (N- (3- (pyrid-4-yl) -propyl) -pyrrolid3- yl) -methyl] -5,6-dimethyl-l-oxo-1,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3. - 95 Yield: 68% of theory, Melting range: 118-127eC (amorphous) Calculated: C 59.03 H 7.54 N 8.98 Cl 22.73 Found: 58.93 7.48 8.84 22.92 Example 94 2-Γ2-(N-(3-(Pyrid-4-yl)-propyl)-piperid-2-yl)-ethvll5.6 -dimethyl -1*3 zdihydro- isoindole io Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2-yl)-ethyl]-5,6-dimethyl-1-oxo-l,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 70% of theory, Melting range: 135-148"C (amorphous) Calculated: C 54.59 H 8.24 N 7.63 Cl 19.33 Found: 54.48 8.26 7.51 19.60 Example 95 2- Γ (N- (l- (Pyrld-4-yl) -methyl) -piperid-3-vl) -methyll5.6-dimethoxy-1.3-dihydro-isoindole-trihvdrochloridetEikvflrafce Prepared from 2- [ (N- (1- (pyrid-4-yl) -methyl) -piperid3- yl)-methyl]-5,6-dimethoxy-phthal imide and lithium aluminium hydride in ether analogously to Exanple 3. Yield: 68% of theory, Melting range: 176-189’C (amorphous) Calculated: C 49.76 H 7.21 N 7.91 Cl 20.03 Found: 49.93 7.12 8.00 20.44 Example 96 2- f (N- (2-(6.7-Dimethoxy-isoquinol-4-vD^ethvl) piperid-3 .-yl) rjnefchyll -5-. 6-dimethyl-1,3-dihydroisoindole-dihydrochloride-semihvdrate Prepared from 2-[(N-(2-(6,7-dimethoxy-isoquinol4-yl)-ethyl)-piperid-3-yl)-methyl]-5,6-dimethyl1- oxo-l,3-dihydro-isoindole and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 22.7% of theory, Melting range: 222-236"C (amorphous) Calculated: C 62.22 H 7.20 N 7.50 Cl 15.83 Found: 62.01 7.64 7.08 15.79 Example 9.7. 2- Γ (N- (l- (Pyrid-4-yl) -methyl) -piperid-3-vl) -methyl 15.6- methylenedioxy-1.3-dihvdro-isoindolerrihydro-chloride- semihydrate Prepared from 2-[(N- (1-(pyrid-4-yl)-methyl)-piperid3- yl)-methyl]-5,6-methylenedioxy-phthalimide and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 55% of theory, Melting range: 215-225°C (amorphous) Calculated: C 53.68 H 6.22 N 8.94 Cl 22.63 Found: 53.60 6.45 8.65 22.28 Example 98 2- Γ (N- (3- (Pyrid-4-yl) -propyl) -Pvrrolid-3-vl) -methv_ll-z. 6.7- dimethyl-1.2.3.4-tetrahydro-isoCTuinoline-trihvdrochloride-monohydrate Prepared from 2-[ (N-(3-(pyrid-.4-yl)-propyl)-pyrrolid97 3-yl) -methyl] -6,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 63% of theory, Melting point: 254-256’C Calculated: C 58.71 H 7.80 N 8.56 Cl 21.66 Found: 58.53 7.72 8.25 21.53 Example 39 2-_£(N-J.l·- (Pyrid-4.-yl) rmethyl)—piperid-3.=yl) -methyl·! 6.7-dimethoxy-l. 2.3.4-tetrahydro-isoquinoline-trihvdro_chloxide-dihydrate Prepared from 2- [ (N- (1- (pyrid-4-yl) -methyl) -piperid3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 63% of theory, Melting range: 158-169"C (amorphous) Calculated: C 52.42 H 7.27 N 7.97 Cl 20.18 Found: 52.55 7.49 7.57 20.25 Example -IQfl 2- Γ2- (N- (3- (Pyrid-4-yl) -propyl) -piperid-2rvl)-ethvll6.7-methylenedioxy-1.2.3.4-tetrahydro-isoouinolinetrihydrochloride- trihydrate Prepared from 2-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2-yl) -ethyl] -6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 90% of theory.
Melting range: 108-119’C (amorphous) Calculated: C 52.58 H 7.41 N 7.36 Cl 18.62 Found: 52.56 7.25 7.38 19.49 Example 101 2- Γ(N-(3-(Pyrid-3-yl)-propyl)-piperid-3-yl)-methyll6.7- methylenedioxy-1.2.3.4-tetrahydro-isoauinoline5 dihydrochloride-monohydrate Prepared from 2-[(N-(3-(pyrid-3-yl)-propyl)-piperid3- yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 72% of theory, Melting range: 126-138’C (amorphous) Calculated: C 59.50 H7.28 N 8.67 Cl 14.64 Found: 59.57 7.29 8.49 , 14.51 .
Example J.Q2 2- Γ (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methyl! 6.7- dimethyl-l.2.3.4-tetrahydro-isoauinoline-trihvdro20 chloride Prepared from 2-((N-(3-(pyrid-3-yl)-propyl)-piperid3- yl)-methyl]-6,7-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 59% of theory.
Melting range: 138-154’C (amorphous) Calculated: C 61.66 H 7.86 N 8.62 Cl 21.84 Found: 61.53 8.00 8.64 21.35 .
Example 103 2- Γ (N- (3- (Pyrid-4-yl) -propyl) -pyrrolid-3-vl) -methvll6.7- dimethyl-l-oxo-l.2.3.4-tetrahydro-isoauinoliner dihydrochloride-monohydrate Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-chloromethyl-N-(3-(pyrid-4-yl)99 propyl]-pyrrolidine analogously to Example 2.
Yield: 39% of theory, Melting range: 74-86’C (amorphous) Calculated: C 61.53 H 7.53 N 8.97 Cl 15.13 Found: 61.42 7.62 8.83 15.05 Example-1Q4 2- Γ (N- (3-(Pyrid-3-yl)-propyl)-piperidr3-vl)-methvlLz 6.7-dimethoxy-l-oxo-l. 2.3.4-tetrahydrorjLsocfuinolinez dihydrashlQride-monQhydEatfi Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(benzenesulphonyloxy-methyl-N15 [3-(pyr id-3-yl) -propyl] piperidine in dimethyl sulphoxide with potassium tert.butoxide analogously to Example 2. Yield: 45% of theory, Melting range: 140-148’C (amorphous) Calc. (X 2 HCl x H2O): C 58.36 H 7.25 N 8.16 Cl 13.78 Found: 58.35 7.32 8.04 13.65 Example.105 2- f3-,(N.~ (3- (Pyrid-.4z.yl) -propyl) -piperid-3-yD.zpropylL· 6.7-dimethoxy-l-oxo-l.2.3.4-tetrahydro-isoquinolinedihydroshlgridezdihydratfi Prepared from 2-[3-(pyrid-3-yl)-propyl]-6,7-dimethoxyl-oxo-l, 2,3,4-tetrahydro-isoquinoline and 4-(330 chlorppropyl) -pyridine analogously to Example 1.
Yield: 48% of theory.
Melting range: 85-96eC (amorph) Calculated: C 57.84 H 7.73 N 7.49 Cl 12.65 Found: 57.71 7.91 7.35 13.04 100 Example_lG£ 2- Γ3- (Ν- (?.- (6.7-Dimethoxy-isoquinol-4-vl)-ethyl) pipeKldza-ylLrpwpyll-guTrdimetJiQxy-l-sxQ-n.S «3.4tetrahydro-isoquinoline-dihydrochloride-monohydrate Prepared from 2-[3-(pyrid-3-yl)-propyl]-6,7-dimethoxy1- oxo-l, 2, 3, 4-tetrahydro-isoquinoline and 4-(2chloroethyl)-6,7-dimethoxy-isoquinoline analogously to Example 1.
Yield: 34% of theory, Melting range: 162-171’C (amorphous) Calculated: C 60.17 H 7.10 N 6.57 Cl 11.10 Found: 59.85 7.00 6.86 11.04 Example 107 2- f.(M- (3- (Pyrid-3 zylL-propyl) -piperid-.3=yl).-methyll 6.7- methylenedioxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline and 3-chloromethyl-N-[3(pyrid-3-yl)-propyl]-piperidine analogously to Example 2.
Yield: 60% of theory.
Melting range: 194-196’C (amorphous) Calculated: C 64.92 H 6.81 N 9.46 Cl 7.98' Found: 64.91 6.95 9.67 7.80 Example,-10.8 2- Γ (N- (1- (Pyrid-4-yl) -methyl) -piperid-3-vl),-methyl! 6.7- dimethoxy-l-otxo-l .2.3.4-tetrahvdro-isoauinolinedihydrochloride-monohydrate Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline in dimethylsulphoxide with potassium 101 tert.butoxide and 3-chloromethyl-N-[1-(pyrid-4yl)-methyl]-piperidine analogously to Example 2.
Yield: 41% of theory, Melting range: 142-158"C (amorphous) Calculated: C 56.78 H 6.83 N 8.63 Cl 14.58 Found: 56.45 6.59 8.66 14.62 Example 1Q9 2,-_riIL· (2.-. (6.-7-BimethQxy-isoquinol-4-yl) -.ethy 1).piperidrl-yiJ -methyl] -6.7,- dimethyls 1-oxo-l .2,3,4tetrahydro - i soouinol ine,-:.dihydrochlor ide Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline in dimethylsulphoxide with potassium tert.butoxide and 3-chloromethyl-N-[2- (6,7-dimethoxyisoquinol-4-yl)-ethyl]-piperidine analogously to Example 2.
Yield: 62% of theory, Melting range: 148-162’C (amorphous) Calculated: C 64.27 H 7.01 N 7.49 Cl 12.65 Found: 64.11 7.20 7.59 12.89 Example 11Q 2- Γ2- (N- (3- (Pvrid-4-yl) -propyl) -piperid-2-vl) -ethvl) 6. .7 ^methylenedioxy-l-oxo-J., 2,3,4-tetrahydro^ isoquinoline-dihydrochloride-dihydrate Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and 2-(2-chloroethyl)-N[3-(pyrid-4-yl)-propyl]-piperidine analogously to Exanple 2.
Melting range: 115-128’C (amorphous) Calculated: C 56.59 H 7.03 N 7.92 Cl 13.37 Found: 56.61 6.90 7.84 13.41 102 Example, 111 2-Γ(N- (3-(Pyrid-3-yl)-propyl)-piperid-3-yl) -methvll6.7- dimethyl-l-oxo-l. 2.3. 4-tetrahydro-isogruinolinedihydrochloride-dihydrate Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline in dimethylsulphoxide with potassium tert. butoxide and 3 - chloromethyl-N- [3 - (pyrid- 3 yl)-propyl]-piperidine analogously to Example 2.
Yield: 62% of theory, Melting range: 118-127"C (amorphous) Calculated: C 60.00 H 7.85 N 8.39 Cl 14.16 Found: 60.24 8.07 8.36 14.62 Example-112 2- [,,(N- (3.-,,(,Pyrid-J-ylltBropyl) -pyrrolid=3=yl) -methyll6.7- methylenedioxy-1-oxo-l.2.3.4-tetrahvdroisoquinol ine-dihydrochloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and 3-chloromethyl-N-[3(pyrid-3-yl)-propyl]-pyrrolidine analogously to Exanple 2.
Yield: 26% of theory.
Melting range: 102-113°C (amorphous) Calculated: C 59.22 H 6.27 N 9.01 Cl 15.20 Found: 59.27 6.49 8.92 14.48 Sxample_ll3. 2ζΧ,ίΗτΙ3ζ (Pyrid-4-yl) -propyl) -pyrrolid-3,-yll_-methyl.l 7.8- methylenedioxy-2-oxo-l. 3-dihydro-2H-3-benzazepinex dihydroshloride Prepared from 7,8-methylenedioxy-2-oxo-l,3-dihydro2H-benzazepine and 3-chloromethyl-N-[3-(pyrid-4103 yl)-propyl]-pyrrolidine analogously to Example 2.
Yield: 58% of theory, Melting range: 132-141’C (amorphous) Calculated: C 60.25 H 6.11 N 8.78 Cl 14.82 Found: 60.00 6.40 8.52 14.56 Example 114 2- .r (N- (3- (Pyrid-3.-yl) -propyl ).-j?yrrol id-3-yl ).jzmethyll7.8- dimethoxy-2-oxo-1.3--dihydro^2H-3-benzazepinedihydrochloride-dihydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2Hbenzazepine and 3-chloromethyl-N-[3-(pyrid-3-yl)propyl] -piperidine analogously to Exanple 2.
Yield: 67% of theory, Melting range: 128-134’C (amorphous) Calculated: C 57.34 H 7.21 N 7.71 Cl 13.02 Found: 57.80 7.37 7.92 13.06 Example 13.5 3- Γ (N-13- (Pyrid-3.-yl) -propyl) -piperid-3-yl) -methyll -. 7.8- dimethyl-2-oxo-l. 3-dihydro-2H-3-benzazeplne·dihydrochloride-dihydrate Prepared from 7,8-dimethyl-2-oxo-l,3-dihydro-2Hbenzazepine and 3-chloromethyl-N- [3- (pyrid-3-yl) propyl] -piperidine analogously to Exanple 2.
Yield: 94% of theory, Melting range: 77-86eC (amorphous) Calculated: C 60.92 H 7.67 N 8.19 Cl 13.83 Found: 60.75 7.60 8.37 13.72 104 Example 116 3- Γ2- (N- (3- (Pyrid-4-yl) -propyl) -piperid-2-vl) -ethyl! 7.8- dimethyl-2-oxo-1.3-dihydro-2H-3-benzazepinedihydrochloride Prepared from 7,8-dimethyl-2-oxo-1,3-dihydro-2Hbenzazepine and 2-(2-chloroethyl)-N-[3-(pyrid-4yl)-propyl]-piperidine analogously to Example 2.
Yield: 94% of theory, Melting range: 118-130eC (amorphous) Calculated: C 66.11 H 7.60 N 8.56 Cl 14.45 Found: 65.92 7.86 8.33 14.09 Example 117 3-Γ (N-(2-(6.7-Dimethoxy-isoquinol-4-yl)-ethyl)piperid-3 zyltzmethyil -7.8-dimethoxy-3-oxo-l·.3 =dihydro2H-3 -benzazepine-monohydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and 3-chloromethyl-N-[2-(6,7-dimethoxyisoquinol-4-yl) -ethyl) -piperidine analogously to Example 2.
Yield: 69% of theory.
Melting range: 85-96"C (amorphous) Calculated: C 67.73 H 7.15 N 7.64 Found: 67.96 7.19 7.75 Example 118 3- Γ3ζ.(Ν- (3- (Pyr id-3.-y 1 J,-. propy IL· pipe rid-3.-yi) -propyLl 7.8- dimethoxy-2-oxo-1.3-dihydro-2H- 3 -benzazepine dihydrochloride-monohydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and 3-(3-chloropropyl)-N-[3-(pyrid3-yl)-propyl]-piperidine analogously to Example 2. 105 Yield: 72% of theory, Melting range: 94-106’C (amorphous) Calculated: C 60.64 H 7.45 N 7.57 Cl 12.78 Found: 60.80 7.44 7.46 12.59 Example IIS. 3- Γ2- (N-(3-(fynidT^zylL-jrQpyl) ^piperid.-2-yl) -ethy.13 7.,.8 -methylenedioxy.-2 - oxo.-1.3 -dihydro-2H-3 -benzaaepine-. dihydrochloride-dihydrate Prepared from 7,8-raethylenedioxy-2-oxo-l, 3-dihydro2H-3-benzazepine and 2-(2-chloroethyl)-N-[3-(pyrid4- yl) -propyl] -piperidine in dimethyl sulphoxide and potassium tert .butoxide analogously to Example 2.
Yield: 67% of theory, Melting range: 148-161"C (amorphous) Calculated: C 57.56 H 6.87 N 7.74 Cl 13.07 Found: 57.72 7.03 7.61 13.62 Example. 120 3- f (N- (l- (Pyrid-4-yl) -methyl) -piperid-3-yl) -methvll 7,8-.dime£hyl-.2^PXg-l, 3-dihydrp-2H-3-foenzazepinedihydrochloride -monohydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and 3-chloromethyl-N- [1- (pyrid-4yl) -methyl] -piperidine in dimethyl sulphoxide and potassium tert .butoxide analogously to Example 2.
Yield: 75% of theory, Melting range: 113-127’C (amorphous) Calculated: C 61.79 H 7.13 N 9.01 Cl 15.20 Found: 61.55 7.32 9.04 15.11 106 Example -121 3-Γ(Ν-(3-(Pyrid-4-yl)-propyl)-pyrrolid-3-vl)-methyl!7.8- methylenedioxy-2-oxo-1.3.4.5-tetrahydro-2H3-benzazepine-dihydrochloride-monohvdrate Prepared from 3-[ (N- (3-(pyrid-4-yl)-propyl)-pyrrolid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3-dihydro2H-3H-benzazepine and 10% palladium/charcoal under a hydrogen pressure of 5 bar at ambient temperature analogously to Exanple 5.
Yield: 71% of theory, Melting range: 95-l06eC (amorphous) Calculated: C 57.83 H 6.67 N 8.43 Cl 14.22 Found: 57.67 6.82 8.27 14.05 Example.122 3-Γ2-(N-(3-(Pyrid-4-yl)-propyl)-piperid-2-yl)rethyll = 7.8- dimethyl-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepinedihydrochlQride.7. semihydrate Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2- yl)-ethyl]-7,8-dimethyl-2-oxo-1,3-dihydro-2H3- benzazepine and 10% palladium/charcoal under a hydrogen pressure of 5 bar at 80*C analogously to Example 5.
Yield: 73% of theory.
Melting point: 236-238C Calculated: C 64.65 H 8.04 N 8.37 Cl 14.14 Found: 64.91 8.02 ,8.25 13.92 107 Example 123 3-Γ3-(N-(2-(2-Methyl-pyrid-6-yl)-ethyl)-piperid3-:yl).-propylI -7-..8.-dimethoxy--2.roxo-l. 3.4.5-tetrahydro5 2H-.3-benzazepina-dihydrochloride-jnonQhydrate Prepared from 3-[3-(piperid-3-yl)-propyl)]-7, 8dimethoxy- 2 - oxo -1,3,4,5- tetrahydro- 2H- 3 -benzazepine and 2- (benzenesulphonyloxy-ethyl) -6-methyl-pyridine in 10 dimethylsulphoxide with potassium carbonate at 120"C analogously to Exanple 1.
Yield: 29% of theory, Melting range: 105-113’C (amorphous) Calculated: C 60.42 H 7.78 N 7.55 15 Found: 60.68 7.50 7.42 Example.124 - [ (N-: (.3- (Pyrid=3-yl) -propyl.) Tpiperid-3-yl) -methyll 2o 7.8-dimethoxy-2-oxo-l. 3.4.5-tetrahydro-2H-3-benzazepinedihydrochloride Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid3- yl) -methyl] -7,8-dimethoxy-2-oxo-l, 3-dihydro-2H25 3-benzazepine by hydrogenation at 5 bar hydrogen pressure in ethanol with 10% palladium charcoal at 70C analogously to Exanple 5.
Yield: 52% of theory.
Melting range: 113-122’C (amorphous) Calculated: C 61.17 H 7.30 N 8.23 Found: 61.31 7.50 8.28 108 Example... 125 3- Γ (N- 12-(6.7-Dimethoxy-isoquinol-4-yl) -ethyl) pipexid.z3.-yl)..-methyll -7., 8 rdimeth2O Prepared from 3- [ (N- (2- (6,7-dimethoxy-isoquinol4- yl) -ethyl) -piperid-3-yl) -methyl] -7,8-dimethoxy2- oxo-l,3-dihydro-2H-3-benzazepine by hydrogenation at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70’C analogously to Exanple 5.
Yield: 50% of theory, Melting range: 82-86°C (amorphous) Calculated: C 66.40 H 7.55 N 7.48 Found: 66.26 7.50 7.59 Example.126 3- Γ3- (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -oropyll 7.B-dimethoxy-2-oxo-l. 3.4.5-tetrahvdro-2H-3-benzazepinedihydrochloride-dihydrate Prepared from 3- [3- (N- (3- (pyrid-3-yl) -propyl) -piperid3-yl) -propyl] -7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine by hydrogenation at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 70’C analogously to Exanple 5.
Yield: 64% of theory, Melting range: 106-115’C (amorphous) Calculated: C 58.53 H 7.89 N 7.31 Cl 12.34 Found: 58.46 7.61 7.14 12.57 109 Example 127 3- Γ (Ν- (3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -methvll 7.8-methylenedioxy-2-oxo-1.3.4.5-tetrahvdro-2H. 5 3-benzazepine-dihydrochloride-monohydrata Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid3-yl) -methyl] -7,8-methylenedioxy-2-oxo-1,3-dihydro2H-3-benzazepine at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 80’C analogously to Example 5.
Yield: 81% of theory, Melting range: 126-138’C (amorphous) Calculated: C 58.58 H 6.88 N 8.19 Cl 13.83 Found: 58.43 7.00 7.85 13.71 Example 128 3- Γ2- (N- (3- (Pyrid-4-yl) -propvl) -piperid-2-vl)-ethvl 1.20 7.8 -methylenedioxy- 2 -oxo-1.3.4.5-tetrahvdro-2H- 3 benzazepine - dihydrochloride -monohvdrate Prepared from 3-[2-(N- (3-(pyrid-4-yl) -propyl) -piperid2-yl) -ethyl] -7,8-methylenedioxy-2-oxo-l,3-dihydro25 2H-3-benzazepine at 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 80’C analogously to Example 5.
Yield: 74% of theory, Melting range: 132-146’C (amorphous) Calculated: C 59.31 H 7.08 N 7.98 Cl 13.46 Found: 59.18 7.41 7.80 13.25 110 Example 129 3-f(Ν-(3- (Pyrid-3-yl) -propyl) -piperid-3-vl) -methvll 7.8-dimethyl-2-oxo-1.3.4.5-tetrahydro-2Hz3-benzazepinedihydrochloride Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3-dihydro-2H3-benzazepine and 5 bar hydrogen pressure with 10% palladium/charcoal in ethanol at 8O’C analogously to Example 5.
Yield: 54% of theory.
Melting range: 92-105’C (amorphous) Calculated: C 62.90 H 7.92 N 8.46 Cl 14.28 Found: 63.19 7.90 8.45 14.30 Example .13 Q 3r I (N- (3-..(Pyjifl-4-yl)-pyrrQlid-3--yl) -methyl 1 -7.8-. methylenedioxy-l.3.4.5-tetrahvdro-2H-3-benzazepinetrihydrochloride-monohydrate Prepared from 3-[(N-(3-(pyrid-4-yl)-propyl)-pyrrolid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 73% of theory, Melting range: 96-108’C (amorphous) Calculated: C 55.53 H 6.97 N 8.06 Cl 20.42 Found: 55.06 7.28 ‘ 7.77 20.07 Example 131 3- Γ (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methvll 7.8-dimethoxy-1.3.4.5-tetrahydro-2H-3-benzazepinedihydrochloride 111 Prepared from 3-[(N-(3-(pyrid-3-yl)-propyl)-piperid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 71% of theory, Melting point: 208-210°C Calculated: C 62.89 H 7.91 N 8.46 Cl 14.28 Found: 62.70 7.53 8.22 14.50 Example 132 3- Γ2- (N- (3-(Pyrid-4-yl)-propyl)-pjperid-2-vl) -ethvll 7.8- methylenedioxy-1.3.4. 5-tetrahvdro-2H-3_-benzazepinetrihydrofihlQride Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2- yl)-ethyl]-7,8-methylenedioxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 63% of theory.
Melting range: 123-136’C (amorphous) Calculated: C 58.81 H 7.21 N 7.91 Cl 20.00 Found: 58.51 7.41 7.92 19.86 Example 133 3- Γ(N- (3- (Pyrid-3-yll -propyl) -pjperid-3-vl) -methyll t. 7.8- methylenedioxy-1.3.4.5-tetrahvdro-2H-3-benzazepinetrihydrochloride-semihvdrate Prepared from 3- [ (N- (3- (pyrid-3-yl) -propyl) -piperid3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 75% of theory, Melting range: 126-138’C (amorphous) - 112 Calculated: C 57.09 H 7.10 N 7.99 Cl 20.22 Found: 57.05 7.32 8.05 20.37 Example 134 3- Γ2- (N- (3- (Pyrid-4-yl) -propyl) -piperid-2rvl) -ethvl 1 7.8-dimethyl-1.3.4.5-tetrahydro-2H-3-benzazepinetrihydrochloride Prepared from 3-[2-(N-(3-(pyrid-4-yl)-propyl)-piperid2- yl)-ethyl]-7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 92% of theory, Melting point: 180-182’C Calculated: C 62.96 H 8.22 N 8.16 Cl 20.65 Found: 63.00 8.29 8.16 20.34 Example ...135 - Γ (N- (3- (Pyrid-3-yl) -propyl) -piperid-3-yl) -methvl1_7.8-dimethyl-1.3.4.5-tetrahydro-2H-3-benzazepinetrihydrochloride Prepared from 3-[ (N-(3-(pyrid-3-yl)-propyl)-piperid3- yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 81% of theory.
Melting range: 184-196’C (amorphous) Calculated: C 60.17 H 8.16 N 8.10 Cl 20.49 Found: 60.28 8.25 8.00 20.39 Example 136 3- Γ2- (N- (2- (6-Methoxy-naphth-2-yl)-ethyl) -piperid-. 2-yl)-ethyl!-7.8-dimethoxy-2-oxo-l.3.4.5-tetrahydro2H-3 -benzazepine-hydrochloride 113 Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(6-methoxy-naphth-2-yl) -ethyl bromide analogously to Example l.
Yield: 20% of theory, Melting point: 158-160°C Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.40 7.56 5.17 6.62 io Example.137 3-(2-(N-(2-(5-Methyl-6-methoxv-naphth-2-vl)-ethvl)piperid-2-yl)-ethyl 1 -7.8-dimethoxy-2-oxo-l.3.4.5tetjahydro- 2H- 3 ^benzazepine-hydrochloride Prepared from 3- [2- (piperid-2-yl) -ethyl] -7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(5-methyl-6-methoxy-naphth-2-yl)-ethyl bromide analogously to Example 1.
Yield: 28% of theory.
Melting point: 140-143®C Calculated: C 69.88 H 7.64 N 4.94 Cl 6.25 Found: 69.06 7.57 4.84 6.44 Example. 138 3- f2.- (N-.(2- (Naphthyl?l-oxy)-ethyi)--jaiperid-2-y3LLethy11-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H3-benzazepine-hydrochloride 30 Prepared from 3- [2- (piperid-2-yl, -ethyl] -7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(naphthyl-l-oxy) -ethyl bromide analogously to Example 1 Yield: 27% of theory, Melting point: 146-148’C Calculated: C 69.06 H 7.29 N 5.20 Cl 6.58 Found: 69.00 7.07 5.31 6.68 114 Example 139 3- Γ2- (N- (2- (Naphth-l-yl) -ethyl) -piperid-2-vl) - ethvl 1 7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine5 hydrflchloEide Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(naphth-l-yl)-ethyl bromide analogously to Exanple 1.
Yield: 24% of theory.
Melting point: 148-150eC Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 70.92 7.44 5.57 7.06 Example 140 3- Γ2- (N- (4- (Naphthyl-2-oxy) -butyl) -piperid-2-vl) ethyl! -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2Hbenzazepine-hydrochloride Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy2 - oxo -1,3,4,5-tetrahydro-2H-3-benzazepine and 4(naphthyl-2-oxy) -butyl bromide analogously to Exanple 1. Yield: 39% of theory, Melting point: 112-114’C Calculated: C 69.88 H17.64 N 4.64 Cl 6.25 Found: 69.69 7.58 4.82 6.52 BxampJ,e 141 3- Γ2- (N- (2- (Naphth-2-yl) -ethvl)-piperid-2-vl) -ethvl! 7.8-dimethoxy-2-oxo-1.3.4.5- tetrahydro-2H-3 -benzaz.epine=.
Prepared from 3-[2-(piperid-2-yl)-ethyl]-7,8-dimethoxy2 - oxo-1,3,4,5-tet rahydro-2H-3-benzazepine and 2(naphth-2-yl)-ethyl bromide analogously to Exanple 1.
Yield: 41% of theory. 115 Melting point: 120-122°C Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 71.10 7.31 5.40 7.05 Example 142 3- Γ2- (N- ((2-Methyl-naphth-l-yl) -methvl) -piperid2-ylJ -ethyl! -7., 8-dimethoxy-2-oxo--1.3 .JUSztetrahydro2H-3-benzazepine-hydrochloride Prepared from 3- [2- (piperid-2-yl) -ethyl] -7,8-dime thoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 1chloromethyl-2-methyl-naphthalene analogously to Example 1.
Yield: 24% of theory, Melting point: 144-146’C Calculated: C 71.18 H 7.51 N 5.36 Cl 6.78 Found: 70.93 7.38 5.48 6.89 Example 143 - Γ (N- (2 - (Naphth-2-yl) -ethyl) -hexahydro-azepin3-yl) -methyl! -7.8-dimethoxy-2-oxo-1.3.4.5 τ tet rahydro2H-3-hentazepinerhydrochloride Prepared from 3-[ (hexahydro-azepin-3-yl)-methyl]7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2-(naphth-2-yl)-ethyl bromide analogously to Exanple 1.
Yield: 58% of theory, Melting point: 204-205eC Calculated: C 71.18 H 7.52 N 5.36 Cl 6.78 Found: 71.41 7.51 5.35 6.50 116 Example 144 3- Γ (N- (2- (Naphth-2-yl) -ethyl) -piperid-3-yl) -methyll 7.8- dimethoxy-2-QXQ-l,3,4« 5-tefcrahydyp-2H=3-benzazepine^ hydrochloride Prepared from 3 - [ (piperid-3-yl) -methyl] -7, 8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(naphth-2-yl)-ethylbromide analogously to Exanple 1. Yield: 35% of theory, Melting point: 239-240’C Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.70 7.10 5.46 7.16 Example ...145 3- .J.(N=.il8aphthz2-yll -methyl) -piperid-3 rylJ-=methyl] 7.8- dimethoxy-2-oxo-l.3.4.5-tetrahydro-2H-3-benzazenine Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2bromomethyl-naphthalene analogously to Exanple 1.
Yield: 27% of theory, Melting point: 176-177’C Calculated: C 75.95 H 7.47 N 6.11 Found: 76.11 7.28 6.10 Example .146 3- r (N- (4- (Naphthyl-2-oxy) -butyl) -piperid-3-yl) methyl!-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro2H-3 -benz azepine-hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 4(naphthyl-2-oxy) -butylbromide analogously to Exanple 1. Yield: 24% of theory, Melting point: 196-197’C - 117 Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.30 7.36 4.99 6.56 Example,. 147. 3- Γ (N- (4- (Naphth-l-vl) -ethvl) -pj.perid-3-vl) -methvll 7.8-dimethoxy-2-oxo-1.3 .4. 5-tetrahvdro-2H-_3-benzazepinehydrochloride IQ prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(naphth-l-yl)-ethyl bromide analogously to Example l. Yield: 18% of theory, Melting point: 230-231’C Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.71 7.07 5.67 6.99 Example 148 3- f (N- (2- (Naphthyl-l-oxyL-ethyl) -piper.id-3-yD -methyll -7.8-dimethoxy-2-oxo-l. 3.4,_5-tetrahvdro2H-3 -benzazepine-hydrQchlQEide Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy25 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(naphthyl-l-oxy)-ethyl bromide analogously to Example 1.
Yield: 40% of theory, Melting point: 214-215"C Calculated: C 68.62 H 7.10 N 5.34 Cl 6.75 Found: 68.40 7.10 5.21 6.77 Example-142. 3- f (Nz.( (2 -Methyl -rjaaphth-lT^X) =methyl) -pipegidz3_ yl) -methyl! -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro2H-3-benzazepine-hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy118 2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 1chloromethyl-2-methyl-naphthalene analogously to Exanple 1.
Yield: 67% of theory, Melting point: 242-243’C Calculated: C 70.78 H 7.33 N 5.50 Cl 6.96 Found: 70.50 7.22 5.34 6.89 Example 150 IQ 3- Γ(N-(2-(6-Methoxy-naphth-2-vl)-ethvl)-piperid3-yl)-methyl 1-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro2H-3-benzazepine-hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy2- oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 2(6-methoxy-naphth-2-yl) -ethyl bromide analogously to Exanple 1.
Yield: 50% of theory, Melting point: 156-157’C Calculated: C 74.07 H 7.62 N 5.57 Found: 73.90 7.55 5.64 Bxample..l51 3- Γ(N-(2-(S-Methyl-6-methoxy-naphth-2-vl)-ethvl)pjperid-3-yl)-methyl!-7.8-dimethoxy-2-oxo-1.3.4.5tetrahvdro-2H-3-benzazepine-hydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dime thoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(5-methyl-6-methoxy-naphthyl)-ethyl bromide analogously to Exanple 1.
Yield: 53% of theory, Melting point: 240-241’C Calculated: C 69.48 H 7.47 N 5.06 Cl 6.41 Found: 69.58 7.48 5.00 6.54 119 Example-152. 2- ΓΝ- (2-(3.4-Dimethoxy-phenyl)-ethvl)-piperid-3yl)-methvl)-5.6-dimethoxv-l-oxo-l.3-dihvdro-isoindole5 hydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-5,6-dimethoxy1,3-dihydro-isoindole and 2-(3,4-dimethoxy-phenyl) ethyl bromide analogously to Exanple 1.
Yield: 68% of theory.
Melting point: 225-226C Calculated: C 63.60 H 7.18 N 5.20 Cl 7.22 Found: 63.61 7.30 5.70 7.44 Example .153 2- f(N-(2-(6-Methoxy-naphth-2-yl)-ethyl)-piperid3- yl) -methyl!-5.6-dimethoxy-1-oxo-l.3-dihydro-isoindolehydrochloride Prepared from 2-[(piperid-3-yl)-methyl]-5,6-dimethoxy1- oxo-l,3-dihydro-isoindole and 2-(6-methoxy-naphth2- yl)-ethyl bromide analogously to Exanple 1.
Yield: 75% of theory, Melting point: 234-236’C Calculated: C 68.16 H 6.90 N 5.48 Cl 6.94 Found: 68.10 7.10 5.39 7.10 Example, .154. 2-J IN- (2- (Naphthyl-1-oxy) -ethyl) -piperid73,-:.yl) methyll -5.6-dimethoxy-1-oxo-l.3-dihvdro-isoindolehydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethoxy1-oxo-1,3-dihydro-isoindole and 2-(naphthyl-1-oxy)ethyl bromide analogously to Exanple 1.
Yield: 60% of theory. 120 Melting point: 150-152’C Calculated: C 67.66 H 6.69 N 5.63 Cl 7.13 Found: 67.50 6.76 5.74 7.54 Example. 155. 2- r (N- (2- (4-Methyl-phenyl) -ethvl) -piperidz3_-vJ.)_methyll-5.6 - dime thoxv-1-oxo-1.3-dihvdror isoindole Prepared from 2-[(piperid-3-yl)-methyl]-5,6-dimethoxy1- oxo-isoindole and 2-(4-methyl-phenyl)-ethyl bromide analogously to Example 1.
Yield: 57% of theory, Melting point: 134-136’C Calculated: C 73.50 H 7.90 N 6.86 Found: 73.40 8.04 7.06 Example 156 2- Γ (N- (2- (3-Methoxy-phenyl) -ethvl) -piperid^^yU methyl] -5.6-dimethoxy-l-oxo-l.3.7dihydrcfJL5.oindQlehydrochloride Prepared from 2- [ (piperid-3-yl)-methyl]-5,6-dimethoxy1- oxo-isoindole and 2-(3-methoxy-phenyl)-ethyl bromide analogously to Exanple 1.
Yield: 54% of theory, Melting point: 226-228°C Calculated: C 65.28 H 7.01 N 6.09 Cl 7.71 Found: 65.30 7.37 5.91 7.61 Example 157 2- f (N- (2- (5-Methyl-6-methoxy-naphtha-yl).-ethvl)r. piperid-3-yl) -methyll -5.6-dimethoxy-1-oxo-1. 3-dihvdro=. isoindole-hydrochloride Prepared from 2-( (piperid-3-yl) -methyl] -5,6-dimethoxy121 1- oxo-l, 3-dihydro-isoindole and 2-(5-methyl-6-methoxynaphth-2-yl)-ethyl bromide analogously to Example 1. Yield: 38% of theory, Melting point: 214-216’C Calculated: C 68.62 H 7.10 N 5.33 Cl 6.75 Found: 68 .«94 7.23 4.98 6.61 Example 158 2- Γ(N-(2- (4-Nitro-phenyl) -ethyl) -piperid-3ryllmethyl! -5.6-dimethoxy-l-oxo-l, 3-dihvdro-isoindolehydrochloride Prepared from 2-[ (piperid-3-yl)-methyl]-5,6-dimethoxy1- oxo-l, 3-dihydro-isoindole and 2-(4-nitro-phenyl)ethyl bromide analogously to Example 1.
Yield: 79% of theory, Melting point: 215-218’C Calculated: C 60.56 H 6.35 N 8.83 Cl 7.45 Found: 60.41 6.26 8.84 7.62 Example -159 3- r (N- (2- (Thien-2-yl) -ethyl) -piperid-3-vl) -methvlL·7.8-dimethoxy-2-oxo-l. 3.4.5-tetrahvdro-2H-3-benzazepine hydrochloride, Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(2-bromo-ethyl)-thiophene analogously to Exanple l. Yield: 43% of theory, Melting point: 232-236’C Calculated: C 1.99 H 7.15 N 6.02 Cl 7.62 S 6.89 Found: 61.90 7.06 5.78 7.96 6.84 Example 16Q 3dT iw·: (27_(ThienL-3-yl) -ethyl) -piperid-3 r.yl) -methyl 1.-. 122 7.8- dimethoxy-2-oxo-Ί. 3.4.5-tetrahydro-2H-3-benzazepinehydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy2- oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and 3(2-bromo-ethyl)-thiophene analogously to Example 1. Yield: 36% of theory, Melting point: sinters at 75-80°, melts at 225-230’C Calculated: C 61.99 H 7.15 N 6.02 Cl 7.62 S 6.89 Found: 62.00 7.08 5.98 8.43 6.62 Example 161 3- f(N-(4-(Thien-2-yl)-butyl)-piperid-3-yl)-methyll 7.8- dimethoxy-2-oxo-1.3.4.5-tetrahvdro-2H-3-benzazepinehydrochloride Prepared from 3-[ (piperid-3-yl) -methyl]-7,8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(4-bromo-butyl)-thiophene analogously to Example 1. Yield: 68% of theory.
Melting range: 190-196’C Calculated: C 63.33 H 7.56 N 5.68 Cl 7.19 S 6.50 Found: 63.18 7.72 5.72 7.29 6.59 Example 162 3- f(N-(2-(BenzoTblfur-2-yl)-ethyl)-piperid-3-yl)methyl! -7.8-dimethoxy-2-oxo-l. 2.3.4-tetrahydro2H- 3 -benzazepine-hydrochloride Prepared from 3 - [ (piperid-3-yl) -methyl] - 7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(2-bromo-ethyl)-benzo [b] furan analogously to Exanple l. Yield: 22% of theory.
Melting point: above 216"C (decomp.) Calculated: C 67.39 H 7.07 N 5.61 Found: 67.14 . 7.36 5.53 123 Example 163 3-f(N-(2-(Benzofblthien-3-yl)-ethvl)-piperid-3yl)-methyl! -7.8-dimethoxy-2-oxo-1.3.4.5-tetrahydro2H-3-benzazepine-hydrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3(2-bromo-ethyl)-benzo [b] thiophene analogously to Example 1.
Yield: 73% of theory.
Melting range: 70-75eC (decomp.) Calculated: C 65.29 H 6.85 N 5.44 Found: 65.10 6.87 5.73 Example 164 3.^1.(M-.C2- (4-Methoxy-benzQfbI thien-3-yl) -ethyl·),.piperid-3-yl)-methyl!-7.8-dimethoxy-2-oxo-1.3.4.5tetrahydrQ-2H-3.7b£ngazepinerhydEochlQJide Prepared from 3-[ (piperid-3-yl) -methyl] -7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3(2-chloroethyl)-4-methoxy-benzo[b]thiophene analogously to Exanple 1.
Yield: 25% of theory, Melting range: 85-105 (decomp.) Calculated: C 63.96 H 6.84 N 5.14 Cl 6.50 S 5.88 Found: 63.95 6.85 4.99 6.53 5.75 Example 165 - f (N- (2 - (6-Methyl sulphonyl oxy-benzo fbl thien-3yl) -ethyl) -piperid-3-yl) -methyl! -7.8-dimethoxy2-oxo-l.3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride Prepared from 3-[ (piperid-3-yl)-methyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3124 [2-(methylsulphonyloxy)-ethyl]-6-methylsulphonyloxybenzo[b]thiophene analogously to Example 1.
Yield: 55% of theory.
Melting point: 90"C (decomp.) Calculated: C 57.18 H 6.12 N 4.60 Cl 5.82 S 10.53 Found: 57.25 6.14 4.50 5.97 10.36 Example 166 3-f (N-(5-(Thien-2-yl)-pentyl)-piperid-3-yl)-methvl! 7.B-dimethoxy-2-oxo-1.3.4. 5-tetrahvdro-2H-3-benzazepinehydrochloride Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dime thoxy15 2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(5-methylsulphonyloxy-pentyl) -thiophene analogously to Example 1.
Yield: 39% of theory, Melting point: 177"C Calculated: C 63.95 H .7.75 N 5.52 Cl 6.99 S 6.32 Found: 63.70 7.92 5.40 7.24 6.62 Example 167 3- Γ (N- (2- (Fur-2-yl) -ethyl) -piperid-3-yl) -methyll 7. B-dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepinehydrochloride Prepared from 3 - [ (piperid-3-yl) -methyl] - 7,8-dimethoxy30 2-oxo-l, 3,4,5 - tetrahydro-2H- 3 -benzazepine and 2(2-methyl sulphonyloxy-ethyl)-furan analogously to Example 1.
Yield: 44% of theory, Melting range: 205-215°C Calculated: C 64.20 H 7.41 N 6.24 Cl 7.90 Found: 64.00 7.45 6.00 7.80 125 Example 168 3-Γ(N-(3-(Fur-2-yl)-propyl)-piperid-3-vl)-methyl7.8- dimethoxy-2-oxo-l.3.4.5-tetrahvdro-2H-3-benzazepinehvdrochloride Prepared from 3-[(piperid-3-yl)-methyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 3(fur-2-yl) -propionaldehyde analogously to Exanple 9. Yield: 11% of theory, Melting point: 201-206’C Calculated: C 64.85 H 7.62 N 6.05 Cl 7.66 Found: 64.88 7.76 5.93 7.55 Example-163 - ((N- (6-.iJhienr2.-yl) -hexyl) - piperid-3 -yl) , jmethyl! 7.8- dimethoxy-2-oxo-l. 3.4.5-tetrahydro-2H-3 -benzazepine^ hydrochloride Prepared from 3 - [ (piperid-3-yl) -methyl] -7,8-dimethoxy2- oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and 2(6-methylsulphonyloxy-hexyl)-thiophene analogously to Exanple 1.
Yield: 27% of theory.
Melting point: 160"C Calculated: C 64.39 H 8.10 N 5.40 Cl 6.79 Found: 64.55 7.90 5.23 7.00 Exanple 170 3- J (N- (3- LlndoL-a-yl) -propyl) - piper id-.3 =y Ik-met hyllz. 7.8-dimethoxy-2-oxo-l. 3.4.5-tetrahvdro-2H-3-benzazepin&z hydrochloride Prepared from 3-[(piperid-3-yl) -methyl]-7,8-dimethoxy2-oxo-l,3,4,5-tetrahydro-2H-3-benzazepine and ΙΟ-me thyl sulphonyl oxy-propyl)-indole analogously to 126 Example l.
Yield: 19% of theory, Melting point: greater than 80’C (decomp.) Calculated: C 60.42 H 6.30 N 6.45 Found: 60.32 6.57 6.67 Example 171 3-Γ(N- (2-(Indol-3-vl)-ethyl)-piperid-3-vl)-methyl! 7.8-dimethoxy-2-oxo-l. 3.4.5-tetrahvdro-2H-3-benzazepinehydrochloride .Prepared from 3- [ (piperid-3-yl) -methyl] -7,8-dimethoxy2 - oxo-1,3,4,5- tetrahydro- 2H- 3 -benzazepine and 3 (2-methylsulphonyloxy-ethyl) -indole analogously to Example l.
Yield: 23% of theory, Melting point: greater than 80’C (decomp.) Calculated: C 65.53 H 6.42 N 7.69 Found: 65.33 6.55 7.80 Example 172 2- f(N- (3--(Naphthyl-2-oxy) -propyl) -hexahyflro-azepin3- yl) -methyl! -6.7-methylenedioxy-l-oxo-isoquinoline Prepared from 6,7-methylenedioxy-l-oxo-l, 3,4,5tetrahydro-isoquinoline and 3-chloromethyl-[N-(3naphthyl-2-oxy) -propyl] -hexahydro-azepine analogously to Example 2.
Yield: 21% of theory, Melting point: 74-76’C Calc, (x 2 H20) : C 64.45 H7.02 N 5.01 Cl 6.34 Found: 64.32 7.20 5.28 6.44 Example 173 2- Γ (N- (3- (Naphth-2_-yl) -propyl).-pyrrolid-3-yl) -methyl! 127 6.7-dimethyl-l-oxo-l. 2.3.4-tetrahydro-isoauinoline Prepared from 6,7-dimethyl-l-oxo-l,3,4,5-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl)N-[3-(naphth-2-yl)-propyl]-pyrrolidine analogously to Example 2.
Yield: 20% of theory, Melting point: 72-76’C Calc, (x H2O): C 72.41 H 7.75 N 5.82 Cl 7.36 Found: 72.27 7.85 5.70 7.96 Example 174 2-ί(N-(3-(5.6-Dimethoxy-naphthyl-2-oxv)-nroovlL·: pyrrolid-3-yl)-methyl!-6.7-dimethoxy-l-oxo-l.2.3.4.ts trahydeo - isoquinol ine-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,3,4,5-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl)N-[3-(5,6-dimethoxy-naphthyl-2-oxy)-propyl]-pyrrolidine analogously to Example 2.
Yield: 9.5% of theory, Melting point: 60-63’C Calc, (x H2O): C 63.20 H 7.01 N 4.75 . Cl 6.02 Found: 63.40 7.04 4.49 6.38 Example 175 2-f(N-(3- (5.6-Dimethoxy-naphthyl-2-oxy)-propyl)hexahydro-azepin-3-yl)-methyl!-6.7-dimethoxy-loxo-l .2.3.4-tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl)N-[3-(5,6-dimethoxy-naphthyl-2-oxy)-propyl]-hexahydroazepine analogously to Example 2.
Yield: 63.2% of theory.
Melting point: 199-201eC 128 Calculated: Found: C 66.15 H 7.23 65.99 7.00 N 4.67 Cl 5.92 4.44 6.02 Example 176 - Γ (N- (3-(5.6 -Dimethoxy-napht.hvL-2 roxvl zPEOpyI).hexahydro-azepin-3-yl) -methvll -6.7-dimethoxv-JL.2^3.4tetrahydro-isQquinQline-dihydrQChlQride Prepared from 2-[(N-(3-(5,6-dimethoxy-naphthyl2-oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -6,7dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 86.3% of theory, Melting point: 114-116’C Calculated: C 61.97 H 7.56 N 4.38 Cl 11.08 Found: 62.05 7.65 4.06 10.84 Example 177 2- f(N-(2-(4-Methoxy-phenyl)-ethvl)-pyrrolid-3-vl)methyl]-6,7-methylenedioxy-1,2,3,4-tetrahydro1 soquinoline-dihydrochloride Prepared from 2-[ (N-(2-(4-methoxy-phenyl)-ethyl) pyrrolid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo1,2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride/tetrahydrofuran analogously to Example 3.
Yield: 86.7% of theory, Melting point: 213-215OC Calculated: C 60.49 H 6.98 N 5.87 Cl 14.88 Found: 60.59 6.96 5.84 14.98 Exanple 178 - Γ (N- (3 - (3.4-Dimethoxy-nhenoxy) -propyl) -pyrrolid3- yl) -methvll -6.7-methylenedioxy-1-oxo-1,2,3.4129 tetrahydro-isoquinoline-hydrochloride Prepared from 1-oxo-l,2,3,4-tetrahydro-6,7methylenedioxy-isoquinoline and N-[3-(3,4-dimethoxyphenoxy) -propyl]-3-benzosulphonyloxymethyl-pyrrolidine analogously to Exanple 2.
Yield: 57.4% of theory, Melting point: 108-110"C Calculated: C 59.76 H 6.74 N 5.35 Cl 7.02 Found: 60.07 6.87 5.23 7.61 Example. 179 2- Γ (N-(2-(4-Methoxy-phenyl)-ethyl)-pyrrolidT3-vl) methyll-6.7-methylenedioxy-l-oxo-l.2.3.4-tetrahydroisoguinollne-hydrochloride Prepared from 1-oxo-l,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinoline and N- [2- (4-methoxyphenyl) -ethyl] 3- benzenesulphonyloxymethyl-pyrrolidine analogously to Exanple 2.
Yield: 54.7% of theory, Melting point: 105-108’C Calculated: C 62.26 H 6.74 N 6.05 Cl 7.97 Found: 62.34 6.74 5.88 8.05 Example 3.80 3-( IN- (2- (6-Methylrpyrifl=.2-yl) -ethyl) - pyrrol id 3r.yl) - methyl 8 zriimethyl-l. 3,4« 5,rtetrahydro-2H3=benzazep.ine. χ -2.*J -ΗΟ-χ,-Η^Ω Prepared from 3- [ (N- (2- (6-methyl-pyrid-2-yl) -ethyl) pyrrolid-3-yl) -methyl] -7,8-dimethyl-2-oxo-l,3,4,5tetrahydro-2H-3 -benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Exanple 3.
Yield: 50% of theory. 130 Melting point: 80-91’C amorphous Calculated: C 61.68 H 8.18 N 8.63 Cl 18.21 Found: 61.55 8.36 8.44 18.10 Example-ISA 3-Γ(N-(2-(6-Methyl-pyrid-2-vl)-ethvll-pyrrolidz 3-yl) -methyl! -7.8-dimethyl-2-oxo-l.. 3.4.5-..tetr.ahvdSQ2Ez3-benzazepine--dihydrc>chlpridezLsemihydEat.e.
Prepared from 3-[(N-(2-(6-methyl-pyrid-2-yl)-ethyl)pyrrolid-3-yl)-methyl]-7,8-dimethyl-2-oxo-1,3-dihydro-, 2H-3-benzazepine with 10% palladium/charcoal at 5 bar hydrogen and at 80eC in ethanol analogously to Exanple 5.
Yield: 92% of theory, Melting point: 86-94’C amorphous Calculated: C 63.41 H 7.66 N 8.87 Cl 14.97 Found: 63.52 7.14 8.81 14.94 Example 182 2- ί .(N·? (3- (6ΓMgthLQxy-naphthyl·z2L·Qxyl-prppyl)^yrEoli.d^ 3- yl) -methyl! -6.7-dimethvl-l-oxo-l, 2.3.4-tetrahvdrpisoguinoline Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl)N- [3- (6-methoxy-naphthyl-2-oxy) -propyl] -pyrrolidine analogously to Example 2.
Yield: 44.7% of theory.
Melting point: 102-104’C Calculated: C 76.24 H 7.68 N 5.93 Found: 75.90 7.62 5.94 131 Example... 18 3 2- Γ(N-(3-(6-Methoxv-naphthvl-2-oxy)-propyl)-pyrrolid3- y.I.) -methyl! -6.7-dimethoxy-1.2.3.4-tetrahydroisoguinoline Prepared from 2-[N-(3-(6-methoxy-naphthyl-2-oxy)propyl) -pyrrolid-3-yl) -methyl] -6, 7-dimethoxy-loxo-l, 2,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran and ether analogously to Exanple 3.
Yield: 68% of theory, Melting point: 106-108"C Calculated: C 73.44 H 7.82 N 5.71 Found: 73.26 7.72 5.81 Example.184 3-f(N-(3-(Indol-3-vl)-propyl)-pyrrolid-3-vl)-methvl!7.8-methylenedioxy-2-oxo-l.3.4.5-tetrahvdro-2H3-benzazepinezmonohydrata Prepared from 3-[(N-(3-(indol-3-yl)-propyl)-pyrrolid3-yl) -methyl] -7,8-methylenedioxy-2-oxo-l, 3-dihydro2H-3-benzazepine with 20% palladium/charcoal at 5 bar hydrogen in ethanol at 80°C analogously to Exanple 5. Yield: 40% of theory.
Melting range: 67-74eC Calculated: C 69.95 H 7.17 N 9.06 Found: 70.00 7.03 8.97 Exanple 185 3-Γ(N- (2- (6-Methvl-pyrid-2-vl) -ethyl) -methvl! -7.8dimethyl-2-oxo-l. 3-dihydro-2H-3 -benzazepine-dihvdrochloride-semihydrate Prepared from 7,8-dimethyl-2-oxo-1,3-dihydro-2H132 3-benzazepine and 3-chloromethyl-N-[2-(6-methylpyrid-2-yl)-ethyl]-pyrrolidine analogously to Example 2. Yield: 81% of theory, Melting point: 86-98’C amorphous 5 Calculated: C 63.68 H 7.27 N 8.91 Cl 15.04 Found: 63.39 7.43 8.87 14.93 Example 186 2-Γ(N-(3-(3-Methvlphenoxy)propyl)-piperid-3-yl)methyl 1 -6.7-dimethoxy-1-oxo-1.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro15 isoquinoline and N- [3-(3-methylphenoxy) -propyl] 3-benzenesulphonyloxymethyl-piperidine analogously to Example 2.
Yield: 75.6% of theory, Melting point: 106-109"C amorphous Calculated: C 63.95 H 7.75 N 5.52 Cl 7.25 Found: 64.66 7.91 5.48 7.28 Example 187 2- Γ (N- (2- (5-Methyl-6-methoxy-naphthyl) -pvrrolid^ 3-yl) -methyl! -6.7-methylenedioxy-l-oxo-l. 2.3.4tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-methylenedioaqr-l-oxo-l/2,3,430 tetrahydro-isoquinoline and 3-(p-toluenesulphonyloxymethyl)-N-[2-(5-methyl-6-methoxy-naphthyl)-ethyl]pyrrolidine analogously to Example 2.
Yield: 27.1% of theory, Melting point: 249-251’C Calculated: C 68.43 H 6.53 N 5.50 Cl· 6.96 Found: 68.47 6.66 5.30 7.16 133 Example 3.88 2- Γ (N- (3- (Naphth-2-yl) -propvl) -pyrrolid-3-vll -methyl! 6.7-dimethoxy-l-oxo-isoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(p-toluenesulphonyloxymethyl) N-[3-(naphth-2-yl)-propyl]-pyrrolidine analogously to Example 2.
Yield: 20.2% of theory, Melting point: 84-86eC Calculated: C 67.88 H 7.26 N 5.46 Cl 6.91 Found: 67.86 7.40 5.40 7.17 Example 189 - Γ (N- (3- (3,4-Dimethoxy-phenoxy) -propyl) -pvrrolid3- yll -methyl! -6.7-dimethoxy-1.2.3.4-tetrahvdroisoquinol ine-dihydro chloride.
Prepared from 2- [ (N- [3-(3,4-dimethoxy-phenoxy) propyl) -pyrrolid-3-yl) -methyl] -6,7-dimethoxy-loxo-l, 2 ,3,4-tetrahydro-isoquinoline and lithium aluminium hydride in diethyl ether and tetrahydrofuran analogously to Exanple 3.
Yield: 92.3% of theory, Melting point: 220-221’C Calculated: C 59.20 H 6.88 N 5.31 Cl 13.44 Found: 59.28 6.97 5.20 13.44 Example.. 12Q - Γ (N- (2 - (3.4-Dimethoxyphenyl) -ethyl) -pvrrolidX-yJD -methyll -6.7-dimethyl-Iroxo-l., 2.3.4-tetrahydro-. isoquinoline Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and N- [2- (3,4-dimethoxyphenyl) -ethyl] 134 3-benzenesulphonyloxymethyl-pyrrolidine analogously to Example 2.
Yield: 70% of theory, Melting point: 168-170’C Calculated: C 73.90 H 8.11 N 6.63 Found: 73.96 8.11 6.55 Example 3.91 2 - r (N- (3- (4-Methoxyphenoxy) -propvl) -piperid-3-vl) methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro15 isoquinoline and N-[3-(4-methoxyphenoxy)-propyl] 3-benzenesulphonyloxymethyl-piperidine analogously to Example 2.
Yield: 78.7% of theory.
Melting point: 98-102°C Calculated: C 63.08 H 7.51 N 5.35 Cl 7.02 Found: 62.87 7.69 5.16 7.28 Example. J.9 2 2- Γ (N- (3- (3-Methoxyphenoxv) -propyl) -piperid-3-vl) methyl! -6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroiRoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydro30 isoquinoline and N- [3-(3-methoxyphenoxy) -propyl] 3-benzenesulphonyloxymethyl-piperidine analogously to Exanple 2.
Yield: 87% of theory.
Melting point: 103-105’C Calculated: C 64.21 H 7.38 N 5.55 Cl 7.02 Found:. 64.00 7.55 5.37 7.12 135 Example 193 2-Γ(Ν-(3-(3-Methoxyphenoxy)-propyl L·: piperid-3-yl)methyl)-6.7-dimethoxy-1.2.3.4-tetrahydro-isoauinoline5 dihydrochloride Prepared from 2-[ (N-(3-(3-methoxyphenoxy)-propyl) piperid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4tet rahydro-isoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Exanple 3.
Yield: 95.4% of theory, Melting point: 170-173’C Calculated: C 60.43 H 7.70 N 5.22 Cl 13.21 Found: 60.50 7.71 4.91 12.97 Example 3.94 2- Γ (N- (2- (3.4-Dimethoxyphenyl) -ethvl) -pyrrolid20 3-yl).--methyll -6,^.7-dimethyl-1.2 «3^ 4ztetKahyflrpT ispquAnQlineTdihydE.QChloxide Prepared from 2-[ (N-(2-(3,4-dimethoxyphenyl)-ethyl)pyrroiid-3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,425 tetrahydro-isoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Exanple 3.
Yield: 94.1% of theory, Melting point: 260-262’C Calculated: C 64.85 H 7.96 N 5.82 Cl 14.73 Found: 64.60 8.11 5.91 14.67 136 Example 195 2-Γ (Ν- (3-(6-Methoxy-naphthyl-2-oxy)-proovll-azacvclooct-3-yl)-methyl!-6.7-dimethoxy-l-oxo-l,2^3,4tetrahydro-isoquinoline-hydrochloride Prepared from 2-[(azacyclooct-3-yl)-methyl]-6,7dimethoxy-l-oxo-1,2,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -6-methoxy-naphthalene analogously to Exanple 1.
Yield: 24.4% of theory.
Melting point: 176-178"C Calculated: C 67.96 H 7.43 N 4.80 Cl 6.08 Found: 67.74 7.29 4.71 6.23 Example 196 3- f.(N- (3- (lndol-3zyl)cpropyl) -pyrrolid-3-yl) -methyll 7.8-dimethyl-2-oxo-l. 3.4.5-tetrahydro-2H-_benzazepinehydrochloride Prepared from 3-[(pyrrolid-3-yl)-methyl]-7,8-dimethyl2-oxo-l,2,3,4-tetrahydro-2H-3-benzazepine and 3(3-benzenesulphonyloxy-propyl)-indole analogously to Exanple 1.
Yield: 62% of theory, Melting point: 106-108’C Calculated: C 69.47 H 7.91 N 8.68 Cl 7.32 Found: 69.57 7.80 8.67 8.51 137 Example 197 3-J (N- (3- (6=Methoxy-naphthyl-2-Qxy)--propyl) -hexahydro-, azepin-3-yl)-methvl1-7.8 - dimethoxy-1.2.3.4-tetrahydro2H-3-benzazepine Prepared from 3- [ (N- (3- (6-methoxy-naphthyl-2-oxy) propyl) -hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy1.2.3.4- tetrahydro-2-oxo-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 26.8% of theory, Melting point: 98-100’C Calc, (x H20): C 71.97 H8.42 N5.09 Found: 72.07 8.23 5.10 Example 198 3-f(N-(3-(6-Methoxy-naphthyl-2-oxy)-propyl) -hexahvdroazepin-3-yl)-methyl!-1.2.3.4-tetrahydro-2-oxo-2H3-benzazepine Prepared from 3- [ (hexahydro-azepin-3-yl) -methyl] t 1.2.3.4- tetrahydro-2-oxo-2H-3-benzazepine and 2(3-chloropropoxy) -6-methoxy-naphthalene analogously to Exanple 1.
Yield: 45% of theory.
Melting point: 109-111’C Calculated: C 72.50 H 7.74 N 5.12 Found: 72.35 7.68 4.93 Example 199 2,-.,LiN.- (3-(-Methoxy.-naphthyl-^-pxy) -propyl) -hexahydroazenin-3-yl) -methyl! -1.3-dihydro-5.6-dimethoxyisoindole Prepared from 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) 138 propyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxyphthalimide and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 49.2% of theory, Melting point: 104-146"C Calculated: C 73.78 H 7.99 N 5.55 Found: 73.63 7.99 5.39 Example 2QQ 3-Γ(N-(3-(Indol-3-yl)-propvl)-pyrrolid-3-vl) -methvll7.8-dimethyl-l.3.4.5-tetrahvdro-2H-3-benzazepinedihydrQchloride.=mQnohydrate Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid3-yl) -methyl] -7,8-dimethyl-2-oxo-lf 3,4,5-tetrahydro2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran/ether analogously to Example 3.
Yield: 65% of theory, Melting point: 168-170"C Calculated: C 66.39 H 8.16 N 8.29 Cl 13.99 Found: 66.29 8.44 8.08 14.08 Example 201 3-f (N- (3- (6-Methoxv-naphthyl-2-oxy) -propyll-hexahydroazepin-3 zyD.zmethyll -1.3.4.5-tetrahyflrQr7 JLmethylenedioxy-2H-3-benzazepine Prepared from 3-[(N-(3-(6-methoxy-naphthyl-2-oxy)propyl)-hexahydro-azepin-3-yl)-methyl]-1,3,4,5tetrahydro-7,8-methylenedioxy-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Example 3.
Yield: 25% of theory, Melting point: 109-lll*C Calculated: C 74.39 H 7.80 N 5.42 Found: 74.27 . 7.94 5.43 139 Example 202 3- Γ (N- (3- (fi-Methoxv-nanht-.hvl-2-oxv) -proovl) -hexahydroazapin- 3 τ.γ.Ι) ,-mathyl· 1-1,3.4.5 - tgtratodrpzJ ,.8methylenedioxy-2-oxo-2H-3-benzazepine-hydrochloride Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]1,3,4,5-tetrahydro-7,8-methylenedioxy-2-oxo-2H3-benzazepine and 2-(3-chloropropoxy)-6-methoxynaphthalene analogously to Exanple 1.
Yield: 68.1% of theory, Melting range: 104-108’C Calc. (X 2 H20): C 65.46 H 7.38 N 4.79 Cl 6.06 Found: 65.60 7.25 5.01 6.43 Exanple 203 2-f(N-(3-(6-Methoxy-naphthyl-2-oxy)-propyl)-hexahvdroazepin-3-yl) -methyl! -6,7-methvlenedioxv^l-oxo-'L^3 tetrahydro-isoquinoline-hydrochloride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]6,7-methylenedioxy-l-oxo-l,3,4,5-tetrahydro-isoquinoline and 2-(3-chloro-propoxy)-6-methoxy-naphthalene analogously to Exanple 1.
Yield: 18.2% of theory.
Melting point: 65-67’C Calc, (x H20): C 65.19 H 6.88 N 4.90 Cl 6.20 Found: 65.20 6.75 4.82 6.54 Example 204 2- Γ(N-(3- (6-Methoxy-naphthvl-2-oxvI-oropyl) -pjperid3- yl) -methyl!-6.7-methylenedioxy-1-oxo-l.2.3..4tetrahydro-isoquinoline Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and 3-.(benzenesulphonyloxy140 methyl)-N-[3-(6-methoxy-naphthalene-2-oxy)-propyl]piperidine analogously to Exanple 2.
Yield: 5.3% of theory.
Melting point: 144-146’C Calculated: C 71.69 H 6.82 N 5.57 Found: 71.52 6.62 5.46 .
Example 205 2-Γ(N-(3-(6-Methoxy-naphthyl-2-oxy)-propyl)-hexahydroazepin-3-yl)-methyl!-5.6-dimethyl-l.3-dihydro-1oxo-isoindole Prepared from 2- [ (N- (3-(6-methoxy-naphthyl-2-oxy) propyl) -hexahydro-azepin-3-yl) -methyl] -4,5-dimethylphthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 18.2% of theory, Melting point: 232-234°C Calc, (x acetone): C 74.97 H 8.14 N 5.14 Found: 74.96 7.90 5.30 Example 206 - Γ (N- (3- (6-Methoxy-naphthyl-2-oxy) -propyl)-hexahvdroazepin-3-yl)-methyl!-6.7-dimethyl-l-oxo-l.2.3.4tetrahydrQ-isoquinoline-hydrochlQride Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro-isoquinoline and 2-(3-chloro-propoxy)-6-methoxy-naphthalene analogously to Exanple 1.
Yield: 17.3% of theory, Melting range: 68-73’C Calc, (x 2 H20): C 67.06 H 7.93 N 4.46 Cl 6.66 Found: 67.05 7.73 4.88 6.18 Example 207 141 2.- f.(8=J3.~ (.6-Methoxy-naphthyl-2-Qxy) -propyl),.,zpiperld3-yl)-methyll-6.7-dimethoxy-l-oxo-l.2.3.4-tetrahvdroisoquinoline Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and 3-(benzenesulphonyloxymethyl)N- [3- (6-methoxy-naphthyl-2-oxy) -propyl] -piperidine analogously to Example 2.
Yield: 12.9% of theory, Melting point: 124-126’C Calculated: C 71.79 H 7.38 N 5.40 Found: 71.83 7.33 5.21 Exanple ,..208 - Γ (N- (3 - (5.6-Dimethoxy-naphthyl-2-oxv)-propyl)hexahydro-azepin-3-yl)-methyl! -1.3.4,5-tetrahydroZ^^xdimeidiQxyziHzldafiiizazeBiae Prepared from 3-[(N-(3-(5,6-dimethoxy-naphthyl2-oxy)-propyl)-hexahydro-azepin-3-yl)-methyl]-1,3,4,5tetrahydro-7,8-dimethoxy-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Exanple 3.
Yield: 29.1% of theory, Melting point: 94-96’C Calculated: C 72.57 H 8.24 N 4.98 Found: 72.56 8.35 4.94 Example,209 2- f (N- (3- (6-Methoxy-naphthyl-2-oxyk-oropyl) -hexahvdroazepin-3-yl) -methyl! -l.3-dihydro-5.6-dimethoxy1-oxo-isoindole Prepared from 2-[ (N- (3-(6-methoxy-naphthyl-2-oxy) propyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxyphthalimide and zinc/glacial acetic acid analogously to 142 Example 4.
Yield: 20.5% of theory, Melting point: 265-267’C Calc, (x 2 H20): Found: C 67.13 H 7.63 N 5.05 67.11 7.64 5.07 Example. 21Q 3- Γ (N- (3- (5.6-Dimethoxy-naphthvl-2-oxv) -propvl)hexahydro-azepin-3-yl)-methyll-1.3.4,5-tetrahvdro7.8-dimethoxy-2-oxo-2H-3-benzazepine Prepared from 3-[ (hexahydro-azepin-3-yl)-methyl]1,3,4,5 -tetrahydro-7,8-dimethoxy-2-oxo-2H-3-benzazepine and 2- (3-chloropropoxy) -5,6-dimethoxy-naphthalene analogously to Example 1.
Yield: 52.4% of theory, Melting point: 129-131’C Calculated: C 70.81 H 7.69 N 4.86 Found: 70.66 7.84 4.63 Example 211 2-Γ (N- (3- (5.6-Dimethoxy-naphthylr2-oxy) -oropvl) hexahydro-azepin-3-yl) -methvll -5.6-dimethoxv^l, 3r dihyflEQzigQindQle.-flihyflEochlQxifle Prepared from 2- [ (N- (3- (5,6-dime thoxy-naphthyl2-oxy) -propyl) -hexahydro-azepin-3-yl) -methyl] -4,5dimethoxy-phthalimide and lithium aluminium hydride in tetrahydrofuran/ether analogously to Exanple 3.
Yield: 48.2% of theory, Melting range: 172-177’C Calc, (x H2O): C 61.43 H 7.41 N 4.47 Cl 11.33 Found: 61.50 7.71 4.59 11.45 143 Example 212 2-Γ(Ν-(3-(5.6-Dimethoxy-naphthyl-2-οχν)-propyl)hexahydro-azepin-3-yl)-methvll-5.6-dimethoxy-1.3dihydro-l-oxo-isoindole-hydrochloride Prepared from 2-I(N-(3-(5,6-dimethoxy-naphthyl2-oxy)-propyl)-hexahydro-azepin-3-yl)-methyl]-4,5dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 36.4% of theory, Melting range: 215-223’C Calc. (X H2O): C 61.87 H 7.30 N 4.50 Cl 5.70 Found: 62.08 7.15 4.55 5.80 Example 213 2- r (N- (3- (Indol-3,7^1) -propyl) -pyrrolid-3-yl).-methyl! 5.6-dimethoxy-1.3-dihydro-isoindole-dihvdrochloridemonohydrate Prepared from 2-[(N-(3-(indol-3-yl)-propyl)-pyrrolid3- yl)-methyl]-5,6-dimethoxy-phthalimide and lithium aluminium hydride in tetrahydrofuran analogously to Example 3.
Yield: 87% of theory, Melting point: 262-264’C Calculated: C 61.17 H 7.30 N 8.23 Cl 13.89 Found: 61.34 7.26 7.92 13.90 Example 214 3-f(N- (3-(5.6-Dimethoxv-naphthvl-2-oxv)-proovl)hexahydro-azepin-3-yl)-methyll-1.3.4.5-tetrahvdro7.8-dimethyl-2H-3-benzazepine-dihydrochloride Prepared from 3-[(N-(3-(5,6-dimethoxy-naphthyl2-oxy,-propyl,-hexahydro-azepin-3-yl)-methyl]-1,3,4,5144 tetrahydro-7,8-dimethyl-2-oxo-2H-3-benzazepine and lithium aluminium hydride/tetrahydrofuran/ether analogously to Exanple 3.
Yield: 76.9% of theory, Melting range*. 138-144°C Calculated: C 67.64 H 8.01 N 4.64 Cl 11.74 Found: 67.73 8.26 4.47 11.50 Example 215 3- Γ (N- (3- (5.6-Dimethoxy-naphthvl-2_-oxy) -propyl·)hexahydro-azepin-3-yl) -methyl! -1.3.4.5-tetrahvdro7.8-dimethyl-2-oxo-2H-3-benzazepine-hydrochloride Prepared from 3-((hexahydro-azepin-3-yl)-methyl] 1,3,4,5-tet rahydro-7,8-dimethyl-2-oxo-2H-3-benzazepine and 2- (3-chloro-propoxy) -5,6-dimethoxy-naphthalene analogously to Exanple 1.
Yield: 47.5% of theory, Melting range: 90-96’C Calc, (x H2O): C 68.15 H 7.90 N 4.67 Cl 5.91 Found: 67.93 7.94 5.05 6.09 Example 216 - Γ (N- (3 - (5.6-Dimethoxv-nanhthvl-2-oxv) -propvl·! piperid-3-yl) -methyl! -6.7-methylenedioxy-l^oxo^ 1.2.3.4-tetrahydro-isoquinoline-hydrochloride Prepared from 2-[(piperid-3-yl)-methyll-6,7methylenedioxy-1-oxo-l,2,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -5,6-dimethoxy’naphthalene analogously to Exanple 1.
Yield: 22.5% of theory, Melting range: 93-98’C Calc, (x H2O) : C 63.42 H 6.69 N 4.77 Cl 6.03 Found: 63.59 6.80 4.70 6.28 145 Example 217 2.- Γ (N- (3- (5.6--Dimethoxy-naphthyl-2.-oxyl-procyl) pyrrol id-3-yl) -methyl! -6.7-methylenedioxy-1-oxo1.2.3,4=tetrahydrQ=isQquinoline-.hydrQchloride Prepared from 2- [ (pyrrolid-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l, 2 ,3,4-tetrahydro-isoquinoline and 2- (3-chloropropoxy) -5,6-dimethoxy-naphthalene analogously to Exanple 1.
Yield: 22.5% of theory, Melting point: 87-90eC Calc, (x H2O): C 62.87 H 6.50 N 4.88 Cl 6.18 Pound: 62.72 6.38 4.93 6.30 Example. .218 2-f (Ν,τ (3- (5, e=PimethPxy-n,aphthyl.-2-pxy) -propyl).-. piperid-3-yl)-methyl!-6.7-dimethyl-l-oxo-l.2.3.4tetrahydrorisoquinolinerhydrochloride Prepared from 2- [ (piperid-3-yl) -methyl] -6,7-dimethyl1- oxo-l, 2,3,4-tetrahydro-isoquinoline and 2-(3chloropropoxy)-5,6-dimethoxy-naphthalene analogously to Exanple 1.
Yield: 21.3% of theory, Melting range: 72-78eC Calc, (x H2O) : C 67.30 H 7.59 N 4.90 Cl 6.21 Found: 67.44 7.74 5.06 6.53 Example .219 2- f (N- (3- (5.6-Dimethoxy-naphthyl-2-oxy) -propvl) hexahydro-azepin-3-yl) -methyl! -6.7-dimethyl-1-oxo1.2.3.4-tetrahydro-isoquinoline-hydrochloride « Prepared from 2- [ (hexahydro-azepin-3-yl) -methyl] 6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 146 2- (3-chloropropoxy) -5, 6-dimethoxy-naphthalene analogously to Example 1.
Yield: 12% of theory, Melting range: 84-90’C Calc, (x H2O): C 67.73 H 7.73 N4.78 Cl 6.06 Found: 67.64 7.81 4.94 6.20 Example 220 - f (N-(2- (4-Methoxy-phenyl) -ethyl) -hexahvdrorazeuinn 3- vl) -methyl! -6.7-methylenedioxy-l-oxo-l. 2.3. 4tetrahydrp-ispquinQline-hydrQChlpride.
Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline and N-[2-(4-methoxy-phenyl)ethyl] -3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 46.7% of theory, Melting point: 101-105’C Calculated: C 62.44 H 7.26 N 5.60 Cl 7.50 Found: 62.62 7.27 5.48 7.66 Example 22.1 2-Γ(N-(3-(4-Methoxy-phenoxy)-propyl)-hexahvdroazfipin=3.-ylL:meXhyn -6.2zmathylenediQxy-:l-i?xQzl.2.3.4tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-2-isoquinoline and N-[3-(4-methoxy-phenoxy)propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 43.8% of theory, Melting point: 123-126’C Calculated: C 62.23 H 7.16 N 5.37 Cl 7.05 Found: 62.42 7.34 5.30 6.94 147 Example-222. 2- Γ IN- (3- (4-Methoxy-phenoxy) -propyl) -hexahydroazepin-3zyl)--methyll-.6 „7-dimethyl,-l-oxorl, 2,3.45 tetrahydro-isoquinoline rhydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydro2- isoquinoline and N-[3-(4-methoxy-phenoxy)-propyl] 3- chloromethyl-hexahydro-azepine analogously to Exanple 10 2.
Yield: 42% of theory, Melting point: 172-173eC Calculated: C 69.04 H 8.07 N 5.75 Cl 7.28 Found: 69.06 8.25 5.57 7.39 Example,.223, 2- Γ (N- (3- (4-Methoxy-phenoxy) -propyl) - hexahydro azepin-3-yl) -methyl! -6.7-dimethoxv-l-oxo-l.2.3.420 tet rahydro-isoquinoline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and N-[3-(4-methoxy-phenoxy)-propyl]3- chloromethyl-hexahydro-benzazepine analogously to 25 Exanple 2.
Yield: 63.3% of theory, Melting range: 115-120’C Calculated: C 62.58 H 7.67 N 5.21 Cl 6.83 Found: 62.44 7.68 4.91 6.81 Exampl£_224. 2- Γ (N- (2- (4-Methoxy-phenyl) -ethvl) -hexahvdro-azeoin3- yl) -methyl! -6.7-dimethoxv-l-oxo-l. 2. 3.4-tetrahvdro35 isQauin.Qline-hydrochloride Prepared from 5,6-dimethoxy-l-oxo-1,2,3,4-tetrahydroisoquinoline and N- [2- (4-methoxy-phenyl) -ethyl] 148 3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 51.6% of theory, Melting point: 110-113’C Calculated: C 61.75 H 7.87 N 5.28 Cl 7.25 Found: 61.84 8.02 5.16 7.22 Example ..,225 2- Γ (N-(2-(3,4-Dimethoxy-phenyl) -ethvl)-hexahydroazepin-3-yl) -methyl! -6.7-dimethoxy-1-oxo-JL.2.3.4tetrahydro-isoquinoline-hydrochloride Prepared from 6,7-dimethoxy-l-oxo-l,2,3,4-tetrahydroisoquinoline and N-[2-(3,4-dimethoxy-phenyl)-ethyl]3- chloromethyl-hexahydro-azepine analogously to Exanple 2.
Yield: 45.5% of theory, Melting point: 107-111’C Calculated: C 62.61 H 7.69 N 5.21 Cl 6.60 Found: 62.78 8.00 5.00 6.43 Example ,.226 2- Γ(N-(2-(3.4-Dimethoxy-phenyl)-ethyl)-hexahydroazepin-3-yl)-methyl!-6.7-dimethyl-l-oxo-l.2.3.4tetrahydro- isocruinol ine-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and N-[2-(3,4-dimethoxy-phenyl)-ethyl]3- chloromethyl-hexahydro-azepine analogously to Exanple 2.
Yield: 44.8% of theory.
Melting point: 162-163°C Calculated: C 66.57 H 8.18 N 5.54 Cl 7.02 Found: 66.67 8.47 5.35 ' 7.11 149 Example 227 - f (Ν- (3- (3-Methyl-phenoxy) -propyl) -hexahydro-azepin3-yl) -methyl! -6.7-methylenedioxy-l-oxo-l.2.3.4tetrahydrQ-is.Qqninoline-hydrochloride, Prepared from 6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and N-[3-(3-methyl-phenoxy)propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 46.8% of theory, Melting point: 159-161’C Calculated: C 65.37 H 7.31 N 5.64 Cl 7.28 Found: 65.44 7.40 5.39 7.23 Example J22 8 2- J IN.-13- (3-Methyl-phenoxy) -pgppyl.) -h.exahydr.o-axep.in= 3- yl) -methyll -6.7-dimethoxy-l-oxo-l. 2 ..3. 4 - tetrahvdror isoqainol ine -hydro,chloride.
Prepared from 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline and N- [3- (3-methoxy-phenoxy) -propyl] 3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 55.2% of theory, Melting point: 107-llleC Calculated: C 65.67 H 7.87 N 5.47 Cl 7.05 Found: 65.47 8.00 5.50 6.97 Example. 222. 2-Γ(N-(3-(3.4-Methylenedioxy-phenoxv) -proovl)-hexahvdro^ azepin-3-yl) -methyl! -6.7-dimethyl-l-oxo-l.2.3.4tetrahydro-isoguinoline-hydrochloride Prepared from 6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and N-[2-(3,4-methylenedioxy-phenoxy) 150 propyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 40.6% of theory, Melting point: 123-126’C Calculated: C 64.78 H 7.57 N 5.39 Cl 6.83 Found: 64.88 7.59 5.29 7.18 Example-23 Q io 2- Γ (N- (3- (3.4-Dimethoxy-phenoxy) -propvlLhexahvdro·azepin-3-yl) -methyll -6.7-dimethoxv-JL^QXQrl·^ 3.^tetrahydxa-isoquinol ine.-hydrochloride Prepared from 6, 7-dimethoxy-l-oxo-l,2,3,4-tetrahydro15 isoquinoline and N-[3-(3,4-dimethoxy-phenoxy)-propyl]3-chloromethyl-hexahydro-azepine analogously to Example 2.
Yield: 30.6% of theory, Melting point: 101-105"C Calculated: C 62.61 H 7.59 N 5.01 Cl 6.46 Found: 62.56 7.76 4.94 6.39 Example. 231 2- f (N- (2- (3.4-Dimethoxv-phenvl)-ethyl)-hexahvdroazepin-3-yl)-methyll -5.6-dimethoxv-l-oxo-l.3-dihvdroisoindole-hydrochlorids Prepared from 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)3Q hexahydro-azepin-3 -yl) -methyl] -5,6-dimethoxyphthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 41.8% of theory.
Melting point: 150-151’C Calculated: C 61.99 H 7.57 N 5.35 Cl 6.57 Found: 61.89 7.48 5.17 6.52 151 Example 232 2- ί (N- (2- (3-Methyl-phenoxy)-propyl)-hexahydro-azepin3- yl) -methyll-6.-dimethQxy-l-QXQ-lJ3^dihydrQ-isoindole-5 hydrochloride Prepared from 2-[(N-(3-(3-methyl-phenoxy)-propyl)hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Exanple 4.
Yield: 88.9% of theory, Melting point: 95-100C Calculated: C 63.95 H 7.75 N 5,52 Cl 7.25 Found: 64.09 7.64 5.35 7.37 Exanple 233 2-Γ(N-(3- (4-Methoxy-phenoxy) -propyl)-hexahvdroazepin-3-yl)-methyll -5.6-dimethoxy-l-oxo-l.3-dihydroisoindole.-JbydrQchlorids Prepared from 2- [ (N- (3- (4-methoxy-phenoxy) -propyl) hexahydro-azepih-3-yl) -methyl] -5,6-dimethoxy-phthalimide and zinc/glacial acetic acid analogously to Exanple 4. Yield: 87.1% of theory, Melting point: 107-112’C Calculated: C 61.99 H 7.51 N 5.35 Cl 7.02 Found: 62.07 7.37 5.28 7.31 Examplfi_2i4 2-f (N- (3.=13. J zMethyifinsdiQxy-phenoxy )-=prQpyl)7hfixahydro·-. agepin=3-yl).7msthyll.-5,6-dimethQxy-.l-QXQ-l»3-.dihyflr.oisoiadplezhydradhlprifle Prepared from 2-[ (N-(3-(3,4-methylenedioxy-phenoxy) propyl) -hexahydro-azepin-3-yl) -methyl] -5,6-dimethoxyphthalimide and zinc/glacial acetic acid analogously to Exanple 4. 152 Yield: 59% of theory, Melting point: 104-107’C Calculated: C 60.38 H 6.94 N 5.20 Cl 7.31 Found: 60.40 7.15 4.95 7.25 Example 235 - Γ (N- (3- (3.4-Methylenedioxy-phenoxv) -propvl) -hexahvdroazepin-3-yl) -methyl! -5.6-dimethoxy-l-oxp-1.3-dihvdrQisoindole-hydrochloride Prepared from 2- [ (N- (3-(3,4-methylenedioxy-phenoxy)propyl) -hexahydro-azepin-3-yl) -methyl] -5, 6-dimethoxyphthalimide and zinc/glacial acetic acid analogously to Example 4.
Yield: 79.4% of theory, Melting point: 112-116’C Calculated: C 62.23 H 7.15 N 5.37 Cl 7.05 Found: 62.16 7.25 4.96 7.03 Example 236 3-f iN-i3,-igyrid=3.7yli -propyl) -hexafaydro-azepinr. 3=yl) -methyl] =3 -dimethoxy-2-oxo-1.3-dihydro-^Hr. 3drenzazepine=dihyflrochlQride-dihydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and N- [3-(pyrid-3-yl)-propyl]-3chloromethyl-hexahydro-azepine in dimethylsulphoxide with potassium tert.butoxide analogously to Exanple 2. Yield: 86% of theory.
Melting point: 106-108’C Calculated: C 58.05 H 7.40 N 7.52 Cl 12.69 Found: 57.94 7.55 7.75 12.42 153 Example-.2 3 7 3- ί (Ν- (3-, (Pyrid-.3.-yL)-p.rapylJ -hexahydro.-azepin3-yl) -methyll -7,8-dimethoxy-2-oxo-l. 3.4. 5-tetrahvdro2 Hr 3 zbenzazepineTdiMgQChlQriderdihydiate, Prepared from 3 - [ (N- (3- (pyrid-3-yl) -propyl) -hexahydroazepin-3-yl) -methyl] -7,8-dimethoxy-2-oxo-1,3-dihydrΟΣΗ-3-benzazepine and 5 bar hydrogen in the presence of 10% palladium on charcoal in dimethylformamide at 80°C analogously to Exanple 5.
Yield: 43% of theory, Melting point: 119-121eC Calculated: C 57.85 H 7.73 N 7.49 Cl 12.65 Found: 57.74 7.79 7.23 12.50 Example. 2.38 - f (N- (3- (Pyrid-3-yl) -propyl) -hexahydro-azepin3-yl)-methyl!-7.8-dimethoxy-1.3.4.5-tetrahvdro2H-3-benzazepine-trihydrochloride-monohvdrate Prepared from 3- [ (N- (3- (pyrid-3-yl) -propyl) -hexahydroazepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Exanple 3.
Yield: 82% of theory.
Melting point: 139-141*C Calculated: C" 57.39 H 7.85 N 7.43 Cl 18.82 Found: 57.42 8.15 7.56 19.04 154 Example 239 2- Γ (N- (1- (Pvrid-3-yl) -methyl) -pyrrolid-3-vl)-methvl1 6.7- methylenedioxy-l-oxo-l. 2.3.4-tetrahvdroisoquinoline-dihydrochloride-dihydrate Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4tetrahydro-isoquinoline and 3-chloromethyl-N-[(pyrid3- yl)-methyl]-pyrrolidine and dimethylsulphoxide with potassium tert.butoxide analogously to Example 2.
Yield: 46% of theory, Melting point: 91-93C Calculated: C 53.17 H 6.16 N 8.85 Cl 14.95 Found: 53.31 5.93 8.71 15.01 Example 240 2- f (N- (1- (ryrid-3-yl) -me£hyl) -pyrrolid-3-yl) -.mst.IiyJ.L6.7- methylenedioxy-1.2.3.4-tetrahydro-isoauinolinetrihydrochloride - 1.5 x hydrate Prepared from 2- [ (N- (1- (pyrid-3-yl) -methyl) -pyrrolid3- yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Example 3.
Yield: 67% of theory.
Melting point: 178-181’C Calculated: C 51.70 H 6.41 N 8.61 Cl 21.80 Found: 51.63 6.62 8.45 21.07 Example 241 3-Γ(N-(2-(6-Methyl-pyrid-2-vl)-ethyl)-hexahvdroazepin-3-yl) -methyll -7.8-dimethoxy-2-oxo-l. 3-dihvdro2H-3-benzazeplne-dihydrochloride-dihydrate Prepared from 7,8-dimethoxy- 2 τοχο-1,3 -dihydro-2H155 3-benzazepine and N- [2- (6-methyl-pyrid-2-yl) -ethyl] 3-chloromethyl-hexahydro-azepine in dimethylsulphoxide with potassium tert .butoxide analogously to Example 2. Yield: 63% of theory, Melting point: 134-136’C Calculated: C 58.05 H 7.40 N 7.52 Cl 12.69 Found: 58.15 7.60 7.45 12.45 Example 242 10 3- ί (N- (2- (6-Methyl-pyrid--2-yl) -ethyl)-.pyrrplid3-yl) -methyl] r 7.8-dimethoxy-2-qxq-J... 3-dihydro-2H3-benzazepine-dihydrochloride x 1.5 hydrate Prepared from 7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and 3-chloromethyl-N- [2-(6-methylpyrid-2-yl) -ethyl] -pyrrolidine in dimethylsulphoxide with potassium tert .butoxide analogously to Example 2. Yield: 61% of theory, Melting point: 78-80’C Calculated: C 57.58 H 6.96 N 8.06 Cl 13.60 Found: 57.40 7.18 8.24 13.39 Example 243 3- Γ (N- (2- (6-Methyl-pyrid-2-yl) -ethyl) -hexahydroazepin-3-vl) -methyl] -7.8-dimethoxy-2-oxo-1.3.4.5tetrahydro-2H-3-benzazepine-dihydrochloride x 2.5 hydrate Prepared from 3-[ (N- (2-(6 -methyl-pyrid-2 -yl) - ethyl) hexahydro-azepin-3-yl) -methyl] -7,8-dimethoxy-2oxo-1,3-dihydro-2H-3-benzazepine and 5 bar hydrogen in the presence of palladium/charcoal and dimethyl35 formamide analogously to Example 5.
Yield: 34% of theory, Melting point: 112-114C Calculated: C 56.93 H · 7.78 N 7.38 Cl 12.45 156 Found: 56.83 8.04 7.43 12.26 Example 244 3-ΚΝ-.Ϊ2·- (6-Methyl-pyrid-2-yl) -ethyl ).-hexahydroazepin-3-yl)-methyl!-7.8-dimethoxv-l.3.4.5-tetrahvdro2Hr 3 zbenzagiepinez trihydrochlorids-dihydrate Prepared from 3- [ (N- (2-(6-methyl-pyrid-2-yl)-ethyl)hexahydro-azepin-3-yl)-methyl]-7,8-dimethoxy-2oxo-1,3,4,5-tetrahydro-2H-3-benzazepine and lithium aluminium hydride in tetrahydrofuran and diethylether analogously to Exanple 3.
Yield: 74% of theory, Melting point: 148-150C Calculated: C 55.61 H 7.95 N 7.20 Cl 18.24 Found: 55.72 8.10 7.03 18.00 Example-245 3-r(N-(2-(6-Methyl-pyrid-2-vl)-ethvl)-pyrrolid-3-yl) methyl! -7.8 - dimethoxy-2.-oxo-1,3^ 4.5.-tetrahydro 2H-3-benzazepine-dihydrochloride-dihydrate Prepared from 3-[(N-(2-(6-raethyl-pyrid-2-yl)-ethyl)pyrrolid-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3dihydro-2H-3-benzazepine and palladium/charcoal in dimethylformamide at 50"C and 6 bar hydrogen pressure analogously to Exanple 5.
Yield:. 28% of theory.
Melting point: 87-90eC Calculated: C 56.38 H 7.38 N 7.89 Cl 13.31 Found: 56.33 7.53 8.09 13.43 157 Example 24.6. 3-Γ(Ν-(2-(6-Methyl-pyrid-2-yl)-ethvl)-pyrrolid3-yl)-methyl1-7.8-dimethoxy-1.3.4.5-tetrahvdro2H-3-benzazepine-trihvdroc.hloride-dihvdra.te Prepared from 7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepine and N-[2-(6-methyl-pyrid-2-yl) ethyl] -3- (benzenesulphonyloxymethyl) -pyrrolidine in dimethylformamide and triethylamine analogously to Example 2.
Yield: 42% of theory, Melting point: 225-227’C Calculated: C 54.10 H 7.62 N 7.57 Cl 19.16 Found: 54.18 7.55 7.51 19.30 Examp Le .2.42. 2- F(N-(3- flndol-3-yl).-propyl) -piperid-l-yD-methyll..5.6- dimethoxy-1-oxo-1.3-dihydro-isoindole x 1..5. benzenesulphonate -.trihydrate Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethoxy1- oxo-l, 3-dihydro-isoindole and 3-(3benzenesulphonyloxy-propyl) - indole in dimethylformamide and triethylamine analogously to Exanple 1.
Yield: 45% of theory, Melting point: 87-89eC Calculated: C 58.51 H 6.54 N 5.68 Found: 58.66 6.43 5.34 Example.. 248 2- f (N-- (3-. (I ndol-3-yl).-propyl) -piper id-T-yl)-methy Hr. 6.7- dimethyl-l-oxo-l. 2.3.4-tetrahydro-isoquinoliner benzenesulphonate-dihyflrata Prepared from 2- [ (piperid-3-yl) -methyl] -5,6-dimethyl158 1-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(3benz ene sulphonyl oxypropyl) - indol e in dimethyl f ormamide and triethylamine analogously to Exanple 1.
Yield: 94% of theory, Melting point: 117-119"C Calculated: C 65.46 H 7.27 N 6.73 Found: 65.51 6.91 6.72 Example 249 3- ί (N- (3- (Indol-3-vl) -propyl) -pyrrolid-3-vl)-methyll 7.8- dimethoxy-2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepinehydrQch3.oride-mp,nQhydzate Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3-dihydro-2H3-benzazepine and 5 bar hydrogen in the presence of palladium/charcoal in dimethylf ormamide at 80’C analogously to Exanple 5.
Yield: 58% of theory, Melting point: 128-13O’C Calculated: C 65.16 H 7.42 N 8.14 Cl 6.87 Found: 65.12 7.55 8.11 7.06 Example-25 ft 3-,. Γ IN = (3-.(Indol-3-yl) -prQpyl)=Jiexahydrp-.azepj.n3-yl)-methyl!-7.8-dimethoxy-2-oxo-1.3.4.5-tetrahvdro2H-2Tbenzazepine-mQnohydrafce.
Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]7.8- dimethoxy-2-oxo-l, 3,4,5-tetrahydro-2H-3 -benzazepine and 3-(3-benzenesulphonyloxy-propyl)-indole in dimethylformamide and triethylamine analogously to Exanple 1.
Yield: 49% of theory, Melting point: 56-58’C Calculated: C 70.98 H 8.14 N 8.27 159 Found: 71.08 8.10 8.16 Example 251 3-f(M-(3- (Indol-3-yl) -propyl) -.tiexahydPQ-azepjul·3-yl) -methyll -7.8-methylenedioxy-1.3.4.5-tetrahvdro2H-.3 - benzazepine - dihydrQchlPiJ.de zmonohydrate Prepared from 3-[(N-(3-(indol-3-yl)-propyl)-hexahydroazepin-3-yl) -methyl] -7,8-methylenedioxy-2-oxo-1,3,4,5tetrahydro-2H-3-benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 56% of theory, Melting point: 155-158’C Calculated: C 62.26 H 7.50 N 7.63 Cl 12.88 Found: 62.31 7.82 7.40 12.89 3z-f.lM.-13- (Indol·-:3.-yl,) zpropyl) .-pyrrol id-3-.yl)-methyll 7.8-dimethoxy-l.3.4.5-tetrahydro-2H-3-benzaz.epinedihydrochloride^mpnohydrate Prepared from 3-[ (N-(3-(indol-3-yl)-propyl)-pyrrolid3-yl) -methyl] -7,8-dimethoxy-2-oxo-l, 3,4,5-tetrahydro2H-3 -benzazepine and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Example 3.
Yield: 60% of theory, Melting point: 125-128’C Calculated: C 62.44 H 7.67 N 7.80 Cl 13.16 Found: 62.35 7.87 7.59 13.67 160 Example 25,3 - Γ (N- (3-(Indol-3-vl) -propyl) -piperid-3-vl) -methvl! 6.7- dimethyl-l.2.3.4-tetrahydro-isoquinoline-dihvdrochlQride.TmQnQhydr.afce Prepared from 2-[(N-(3-(indol-3-yl)-propyl)-piperid3-yl) -methyl].-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in diethylether and tetrahydrofuran analogously to Exanple 3.
Yield: 90% of theory, Melting point: 198-201’C Calculated: C 66.38 H 8.16 N 8.29 Cl 14.00 Found: 66.29 8.21 8.46 13.82 Example.. ,254. 3_f (Nr (3--(IndQl-3--:yl} -propyl) -hexahydro-azepinr, 3-yl)-methyl!-7.8-methylenedioxy-2-oxo-1.3.4.5tetrahydro-2H-3-benzazepine-monohydrate Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]7.8- methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H3-benzazepine and 3-(3-benzenesulphonyloxy-propyl)indole analogously to Exanple 1.
Yield: 61.5% of theory, Melting point: 62-64’C Calculated: C 70.84 H 7.59 N 8.55 Found: 70.73 7.59 8.42 Exanple 255 2-r(N- (3-(Indol-3-vl)-propyl)-pyrrolid-3-yl)-methvll 6.7-dimethyl-l.2.3.4-tetrahydro-isoquinoline-dihydrochloride-semihydrate Prepared from 2-[ (N- (3-(indol-.3-yl) -propyl) -pyrrolid161 3-yl) -methyl] -6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydroisoquinoline and lithium aluminium hydride in ether analogously to Example 3.
Yield: 86% of theory, Melting point: 143-145’C Calculated: C 67.06 H 7.92 N 8.69 Cl 14.66 Found: 66.92 8.07 8.48 14.87 Example.256 2- Γ (N- (3- (Indol-3-yl) -propyl) -pyrrolid-3-vl.) -methyl! 6.7-dimethyl-l-oxo-l.2.3.4-tetrahvdro-isomiinQlinehydrochloride x .1.5 -hydrate.
Prepared from 2-[ (pyrrplid-3-yl)-methyl]-6,7-diraethyl1-oxo-l,2,3,4-tetrahydro-isoquinoline and 3-(3benzenesulphonyloxy-propyl)-indole analogously to Example 1.
Yield: 67% of theory, Melting point: 117-120’C Calculated: C 67.69 H 7.78 N 8.77 Cl 7.40 Found: 67.62 7.80 8.72 7.93 Example 257 Tablets containing 7.5 mg of 3-Γ (N-(2-_(naphth-2-_ yJJ-ehhyll^piperid-=3TyJJ zmefchyll -7,8-dimathoxyr, 2.-ΡΧΟ.-14.5=tetrahydro-2H-3 -benzazeplne-hydrochlorlde Composition: tablet contains: Active substance Com starch Lactose 7.5 mg 59.5 mg 48.0 mg Polyvinylpyrrolidone Magnesium stearate 4.0 mg l,.Q.mg 120.0 mg 162 Method Qf .preparation The active substance, com starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is pushed through a screen with a mesh size of 1.5 mm and dried at about 45C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The final mixture is compressed in a tablet press with dies 7 mm in diameter provided with a dividing notch to form tablets.
Weight of tablet: 120 mg.
Example-258 Coated tablets containing 5 mg of 3-f(N-(2-(naphth2-yl) -ethyl ).7piperid^3--yl.)-me.thyl.1 -7.8.--dimeh,hQxy— 2-oxo-1.3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride tablet core contains: Active substance 5.0 mg Com starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mg 80.0 mg Method of JrepacatiQB The active substance, com starch, lactose and polyvinylpyrrolidone are throughly mixed and moistened with water. The moist mass is forced through a 1 mm screen, dried at about 45°C and then the granulate is passed through the same screen. After magnesium stearate has been added, convex tablet cores with a diameter of 6 mm are compressed in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax. 163 Weight of coated tablet: 130 mg.
Example 259 Ampoules containing 5 mg of 3-Γ(N-(2-(naphth-2-vl)5 piperid-3-yl)-methyll-7.8-dimethoxy-2-oxo^l.3,4.5tetrahvdro-2H-3-benzazepin-2-one-hvdrochloride ampoule contains: Active substance 5.0 mg Sorbitol 50.0 mg Water for injections ad 2.0 mg Method-of Preparation In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol.
After being filtered through a diaphragm filter the solution is transferred under a current of N2 into purified and sterilized ampoules and auto-claved for 20 minutes in a jet of steam.
Example 260 Suppositories containing 10 mg of 3-Γ(N-(2-(naohth2-yl)-ethyl)-piperid-3-yl)-methyll -7.8-dimethoxy2-oxo-l. 3.4.5-tetrahydro-2H-3-benzazepine-hydrochloride 1 suppository contains: Active substance 0.010 g Hard fat (e.g. Witepsol H 19 and W 45) 1.690 σ 1.700 g Method of Preparation The hard fat is melted. At 38C the ground active substance is homogeneously dispersed in the melt. It is 164 cooled to 35’C and poured into slightly chilled suppository moulds.
Example,_2 61 Drops solution containing 10 mg of 3-Γ(N-(2-(naphth2-yl) -ethyl) -piperid-3-yl) -methyll -7.8-dimethoxv2-oxo-l. 3.4.5-tet rahydro-2 H-3-benz azepine-hydrochloride 100 ml of solution contain Active substance Hydroxyethylcellulose Tartaric acid Sorbitol solution with 70% dry matter Glycerol Benzoic acid Dist. water ad 0.2 g 0.15g 0.1 g .0 g 10.0 g 0.15g 100 ml Method of Preparation The distilled water is heated to 70C. The hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The mixture is cooled to ambient tenperature and the glycerol and sorbitol solution are added with stirring. At ambient tenperature the active substance is added and stirred until completely dissolved. The syrup is then evacuated of any air with stirring.

Claims (6)

1. Cyclic amine derivatives of general formula (I) wherein A represents a -CH 2 -, -CH 2 ~CH 2 - or -CH=CH- group, x B represents a -CH 2 ~, , -CO- or -CH 2 CO group, whilst the carbon atom marked x is linked to the phenyl nucleus, E represents a straight-chained C x . 3 -alkylene group, G represents a straight-chained Cx.g-alkylene group, wherein a methylene group, linked to an aromatic or heteroaromatie group R, of a straight-chained C 3 . 6 a Iky lene group may be replaced by an oxygen atom, or by a methyl imino or ethyl imino group, m represents the number 1, 2, 3, 4, 5 or 6 and n represents the number 0, 1, 2 or 3, although n + m must represent the number 3, 4, 5 or 6, R 1 represents a methyl or methoxy group, R 2 represents a methyl or methoxy group or R^ and R 2 together represent a methylenedioxy group and R represents an optionally methyl-substituted furyl, 166 thienyl, pyridyl, benzo[b]furyl or benzo[b]thienyl group, a benzo[b]thienyl group substituted by a halogen atom or by a methoxy or methanesulphonyloxy group, an indolyl or N-methyl-indolyl group optionally substituted by a hydroxy, methoxy or benzyloxy group, a dimethyl-thienyl or dimethoxy-isoquinolyl group, a naphthyl group optionally mono- or disubstituted by methyl or methoxy groups, whilst the substituents may be identical or different,., or, if B represents a -CH 2 ~ or -CO- group, a phenyl group optionally substituted by a methylenedioxy group, a phenyl group mono- or disubstituted by a chlorine or bromine atom or methyl or methoxy groups, whilst the substituents may be identical or different, a phenyl group substituted by a hydroxy, benzyloxy, methanesulphonyloxy, trifluoromethanesulphonyloxy, trifluoromethyl, trifluoromethoxy, nitro, amino, acetamido, methanesulphonylamino or bis (methanesulphonyl) amino group, or a trimethoxyphenyl, tetramethylphenyl or dihaloaminophenyl group, the enantiomers, diastereomers, N-oxides and acid addition salts thereof.
2. Cyclic amine derivatives of general formula (Ia) (la) wherein R, R^, R 2 , A, Β, E, G, m and n are defined as in claim 1, the enantiomers, diastereomers, N-oxides and acid addition salts thereof. 167
3. Cyclic amine derivatives of general formula Ia according to claim 2, wherein A represents a -CH 2 CH 2 - group, x B represents a -CH 2 -CH 2 _, -CO- or -CH 2 CO- group, wherein the carbon atom designated x is linked to the phenyl nucleus, E represents a methylene or ethylene group, G represents a straight-chained C 2 _ 4 -alkyl ene group, wherein a methylene group of a straight-chained C 3 _ 4 alkylene group, linked to an aromatic or heteroaromatie group R, may be replaced by an oxygen, R 1 represents a methoxy group, R 2 represents a methoxy group or R 1 and R 2 together represent a methylenedioxy group, m represents the number 2, 3 or 4, n represents the number 1 and R represents a naphth-2-yl, 6-raethoxy-naphth-2-yl, 5-methyl-6-methoxy-naphth-2-yl, thien-2-yl, 6-methylpyrid-2-yl, benzo[b]fur-2-yl or benzo[b]thien-3-yl group or, if B represents a -CO- group, a 4-methoxyphenyl or 3,4-dimethoxyphenyl group, the enantiomers, diastereomers and acid addition salts thereof.
4. Cyclic amine derivatives of general formula (Ia) according to claim 2 168 a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) methyl] -7, 8-dimethoxy-2-oxo-l, 3,4,5-tetrahydro2H-3-benzazepine, b) 3- [ (N- (2- (5-methyl-6-methoxy-naphth-2-yl) -ethyl) piperid-3-yl) -methyl] -7,8-dimethoxy-2-oxo-l, 3,4,5tetrahydro-2H-3-benzazepine, c) 3-:(2- (N- (2 - (6-methoxy-naphth-2-yl) -ethyl) -piperid2- yl)-ethyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, d) 2- [ (N- (2-(6-methoxy-naphth-2-yl) -ethyl) -hexahydroazepin-3-yl)-methyl]-6,7-methylenedioxy-l-oxo-l,2,3,4tetrahydro-isoquinoline, e) 2-[(N-(2-(naphth-2-yl)-ethyl)-hexahydro-azepin3- yl)-methyl]-6,7-methylenedioxy-1-oxo-l,2,3,4tetrahydro-isoquinoline, f) 2- [ (N- (2-(3,4-dimethoxy-phenyl)-ethyl)-piperid3-yl)-methyl]-6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline, g) 2-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperid3-yl)-methyl]-6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline, h) 2 - [ (N- (3- (4-methoxy-phenoxy) -propyl) -piperid3-yl)-methyl]-6,7-dimethyl-l-oxo-l, 2,3,4-tetrahydroisoquinoline, i) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] 7,8-dimethoxy-2-oxo-l, 3,4,5-tetrahydro-2H-3-benzazepine, k) 3- [ (N- (2- (benzo [b] fur-2-yl) -ethyl) -piperid-3yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro169 2H-3-benzazepine, l) 3-[(N-(2-(benzo[b]thien-3-yl)-ethyl)-piperid3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro5 2H-3-benzazepine, m) 2-[(N- (3-(6-methoxy-naphth-2-yl-oxy)-propyl)pyrrolid-3-yl)-methyl]-6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro-isoquinoline and n) 2-[(N- (2-(6-methoxy-naphth-2-yl)-ethyl)-hexahydroazepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4t et rahydro - i s oquinol ine, 15 the enantiomers, diastereomers and acid addition salts thereof. 5. Cyclic amine derivatives of general formula (Ia) according to claim 2 a) 3- [ (N- (2- (naphth-2-yl) -ethyl) -piperid-3-yl) methyl]-7,8-dimethoxy-2-oxo-l,3,4,5-tetrahydro2H-3-benzazepine, 25 b) 2-[ (N-(3-(4-methoxy-phenoxy)-propyl)-piperid3-yl) -methyl] -6,7-dimethyl-l-oxo-l,2,3,4-tetrahydroisoquinoline , c) 3- [ (N- (4- (thien-2-yl) -butyl) -piperid-3-yl) -methyl] 30 7,8-dimethoxy-2-oxo-l, 3,4,5 - tetrahydro-2H-3-benzazepine, d) 2- [ (N- (3- (6-methoxy-naphthyl-2-oxy) -propyl) pyrrol id-3-yl) -methyl] -6,7-dimethoxy-l-oxo-l,2,3,4tetrahydro- isoquinoline, e) 2- [ (N- (2- (6-methoxy-naphth-2-yl) -ethyl) -hexahydroazepin-3-yl) -methyl] -6,7-methylenedioxy-l-oxo-l,2,3,4170 tetrahydro-isoquinoline, f) 3- [ (N- (2-(4-methoxy-phenyl)-ethyl)-hexahydroazepin-3-yl)-methyl]-7,8-dimethoxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine and g) 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-hexahydroazepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-l,3,4,5tetrahydro-2H-3-benzazepine the enantiomers, diastereomers and acid addition salts thereof. 6. 3-[(N-(2-(Naphth-2-yl)-ethyl)-piperid-3-yl)methyl]-7,8-dimethoxy-2-oxo-1,3,4,5-tetrahydro2H-3-benzazepine, the enantiomers, diastereomers and acid addition salts thereof. 7. Physiologically acceptable acid addition salts of the compounds according to claims 1 to 6 with inorganic or organic acids. 8. Pharmaceutical compositions containing a compound of general formula I according to claims 1 to 6 or a physiologically acceptable acid addition salt thereof according to claim 7 together with one or more inert carriers and/or diluents. 9. Pharmaceutical compositions according to claim 8 suitable for the treatment of sinus tachycardia and ischaemic heart disease. 10. Process for the preparation of a pharmaceutical preparation according to claims 8 and 9, characterised in that a compound according to claims 1 to 6 or a physiologically acceptable acid addition salt thereof according to claim 7 is incorporated in one or more 171 inert carriers and/or diluents by a non-chemical method. 11. Process for the preparation of cyclic amine derivatives according to claims 1 to 7, characterised in 5 that a) a compound of general formula (II) (II) wherein R lX R 2 , A, Β, E, m and n are defined as in claims 1 to 6, is reacted with a conpound of general formula Z 2 - G - R (III) wherein R and G are defined as in claims 1 to 6 and 25 Z 1 represents a nucleophilic leaving group, a hydroxy group or Z 1 together with a hydrogen atom of the adjacent methylene group represents an oxygen atom, or •r b) a compound of general formula (IV) (IV) 172 (V) wherein R^, R 2 , A and B are defined as in claims 1 to 6, is reacted with a compound of general formula (V) Z„ - E / CH 2>m CH \ < CH 2>n wherein R, E, G, m and n are defined as in claims 1 to 6 and Z 2 represents a nucleophilic leaving group, and subsequently, if desired, any protecting group used during the reactions a) to e) to protect reactive groups such as hydroxy, amino, alkylamino or imino groups, is cleaved and/or subsequently, if desired, a compound of general formula I thus obtained wherein R contains a nitro group, is converted by reduction into a corresponding amino compound of general formula 1 and/or a compound of general formula I thus obtained wherein R contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a conpound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or a conpound of general formula I thus obtained is converted into the acid addition salts thereof, more particularly the physiologically acceptable acid 173 addition salts thereof with inorganic or organic acids. 12. Process for preparing cyclic amine derivatives of general formula (I) according to claims 1 to 7 wherein B 5 denotes a -CH 2 - or -CH 2 CH 2 group, characterised in that c) a compound of general formula (VI) (VI) wherein R, R x , R 2 , A, E, G, m and n are defined as in claims 1 to 6 and 20 Β χ represents a -CO- or -CH 2 CO- group, whilst the carbon atom marked x is linked t$ the phenyl nucleus, is reduced, and subsequently, if desired, a compound of general formula 25 I thus obtained wherein R contains a nitro group, is converted by reduction into a corresponding amino compound of general formula I and/or a compound of general formula I thus obtained wherein R 30 contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a compound of general formula I thus obtained which 35 contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or 174 a compound of general formula I thus obtained is converted into the acid addition salts thereof, more particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids. 13. Process for preparing cyclic amine derivatives of general formula I according to claims 1 to 7, wherein A represents a -CH 2 ~ group and -CH 2 CO- group, characterised general formula (VII) B represents a -CO- or in that a compound of I.' CH 2^xd (VII) \ - CH N - G - R wherein R, R lf R 2 , E, G, m and n are defined as in claims 1 to 6 and x B 2 represents a -CO- or -CH 2 CO- group, the carbon atom marked x being linked to the phenyl nucleus, is reduced with nascent hydrogen, and a compound of general formula I thus obtained wherein R contains an amino group is converted by acylation into a corresponding alkanoylamino compound of general formula I and/or a compound of general formula I thus obtained which contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or a compound of general formula I thus obtained is converted into the acid addition salts thereof, more - 175 particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids. 14. Process for preparing new cyclic amine derivatives 5 according to claims 1 to 7, wherein A represents a -CH 2 CH 2 - group and B represents a methylene or carbonyl group, characterised in that (VIII) as in claims 1 general formula wherein R, R 2 , Β, E, G, m and n are defined 20 to 6, and B 3 represents a -CH 2 - or -CO- group, is hydrogenated, and subsequently, if desired, a conpound of 25 I thus obtained wherein R contains an amino group is converted by acylation into a corresponding alkanoylamino conpound of general formula I and/or a conpound of general formula I thus obtained which 3Q contains at least one chiral centre is resolved into its diastereomers or its enantiomers and/or a conpound of general formula I thus obtained is converted into the acid addition salts thereof, more 35 particularly the physiologically acceptable acid addition salts thereof with inorganic or organic acids. - 176 15. Process for the preparation of cyclic amine derivatives as claimed in any of claims 11 to 14 substantially as described herein with reference to the Examples.
5. 1
6. Cyclic amine derivatives whenever prepared by a process as claimed in any of claims 11 to 15.
IE155988A 1987-05-25 1988-05-24 New cyclic amine derivatives pharmaceutical compositions containing these compounds and processes for their preparation IE68842B1 (en)

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DK282188A (en) 1988-11-26
EP0292840B1 (en) 1995-08-09
IL86477A (en) 1992-07-15
IN169514B (en) 1991-11-02
EP0292840A2 (en) 1988-11-30
NO171017B (en) 1992-10-05
ATE126225T1 (en) 1995-08-15
ES2076147T3 (en) 1995-11-01
IE881559L (en) 1988-11-25
FI882418A0 (en) 1988-05-23
DE3717561A1 (en) 1988-12-08
JPS6445381A (en) 1989-02-17
SU1561823A3 (en) 1990-04-30
PT87567A (en) 1989-05-31
GR3017550T3 (en) 1995-12-31
HUT46906A (en) 1988-12-28
NO882258L (en) 1988-11-28
DK282188D0 (en) 1988-05-24
EP0292840A3 (en) 1990-04-11
FI94343C (en) 1995-08-25
HU198201B (en) 1989-08-28
KR880013924A (en) 1988-12-22
DD284678A5 (en) 1990-11-21
JP2634190B2 (en) 1997-07-23
KR960009432B1 (en) 1996-07-19
AU1656288A (en) 1988-12-01
DE3854280D1 (en) 1995-09-14
IL86477A0 (en) 1988-11-15
NZ224756A (en) 1991-02-26
ZA883680B (en) 1990-01-31
CA1287226C (en) 1991-08-06
PT87567B (en) 1992-09-30
FI882418A (en) 1988-11-26
CA1330993C (en) 1994-07-26
AU607765B2 (en) 1991-03-14
NO882258D0 (en) 1988-05-24
NO171017C (en) 1993-01-13
FI94343B (en) 1995-05-15

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